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Lessons for clinical trials from natalizumab in multiple sclerosis

BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7538.416 (Published 16 February 2006) Cite this as: BMJ 2006;332:416

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Natalizumab in multiple sclerosis

We, the U.K. multiple sclerosis natalizumab investigators, feel it is
important to address the issues raised by Dr Chaudhuri in his paper
published in the BMJ on the 18th Feb and the associated editorial [1].

Dr Chaudhuri states that;

(1) “none of the published trials showed convincing evidence of the
efficacy of natalizumab in relapsing multiple sclerosis”.

This is incorrect; both of the exploratory phase 2 studies showed an
impact of natalizumab on the frequency of gadolinium enhancing lesions
[2,3] and in the 6-month study natalizumab had a robust impact on relapse
rate [3].

(2) “The assumption that prolonged periods of monthly infusions of
natalizumab are relatively safe is questionable, because few data are
available from preclinical and clinical studies on the optimal duration of
treatment and long term safety.”

The reason why two phase 3 natalizumab studies were performed and
subjects were asked to volunteer for an open-label extension study was to
ascertain the long-term safety of natalizumab. It was never assumed that
prolonged periods of infusions of natalizumab were safe.

(3) “The FDA did not review the safety data of natalizumab in non-
multiple sclerosis trials.”

All safety data available at the time, regardless of indication, were
submitted to the FDA as part of the new drugs application.

(4) “The data for combination therapy (natalizumab and interferon
beta-1a) were interesting: the annualised relapse rate for interferon beta
-1a alone was slightly worse than for placebo in the natalizumab
monotherapy trial (0.78% and 0.74%), a result that questions the
effectiveness of the drug.”

It is impossible to compare data across these two studies. Firstly,
the disease duration in the subjects in the combination therapy study [4]
was on average longer than those in the monotherapy study [5]; their
relapse rate would be expected to be lower as relapse rate decreases with
disease duration. Secondly, subjects in the monotherapy trial had by
definition failed interferon-beta therapy (one relapse in the last 12
months) [4]; they therefore cannot be compared to interferon-naïve placebo
treated subjects. Thirdly, the impact of natalizumab on relapse rate, MRI
markers of disease activity and disease progression is robust in both
studies [4,5], it is now difficult to question the effectiveness of the
drug.

(5) “Experience with natalizumab highlights the potential risks for
patients in trials of new drugs where knowledge of long term efficacy,
outcome measures, and safety is lacking.”

This is why clinical trials are performed; to define the risk:benefit
ratio of potential new disease-modifying treatments so that subjects with
MS and the clinical team looking after them can make informed decisions.

(6) “The use of natalizumab cannot be justified because the risk of
PML is high and the long term efficacy of the drug is unknown.”

A detailed safety study for possible cases of PML in subjects exposed
to natalizumab in clinical studies has found no further cases and quotes a
risk of PML of approximately 1 in 1000 subjects treated with natalizumab
after a mean of 18 months of therapy [6]. Both the cases of PML in the
subjects with MS were receiving Natalizumab in combination with interferon
-beta-1a. Obviously the risk of PML associated with longer natalizumab
treatment, particularly as monotherapy, is not known. It is important to
put this risk into perspective for clinicians managing people with MS.
Mitoxantrone is widely used as a rescue therapy for subjects with
aggressive MS; the risk of developing treatment-related leukaemia after a
course of mitoxantrone is currently estimated as being approximately 1 in
400 [7].

(7) “Its therapeutic effect on the progression of disability in
multiple sclerosis is not established.”

The impact of natalizumab on the relapse rate, the primary endpoint
at one-year is highly significant, a point at which the impact on
disability was not assessed. The primary endpoint at two years; i.e. the
time to onset of sustained disability progression has now been published.
In the placebo-controlled study natalizumab reduced the risk of sustained
disability progression by 42% over two years compared with placebo (Hazard
ratio=0.58; 95% confidence interval: 0.43, 0.77; P<0.001)[8]. The
cumulative probability of progression, based on Kaplan-Meier analysis, was
17% in the natalizumab treated group and 29% in the placebo treated group
[8]. In the combination therapy study, natalizumab and interferon-β-
1a resulted in a 24 percent reduction in the relative risk of sustained
disability progression compared to interferon-β-1a alone (hazard
ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P = 0.02) [9].
Kaplan–Meier estimates of the cumulative probability of progression at two
years were 23 percent with combination therapy and 29 percent with
interferon-β-1a alone [9].

(8) “Patients who volunteer for clinical trials should not be given
the impression that they have the advantage of receiving new, potentially
effective, safe, and free treatment. Patients should be made aware of the
limitations of knowledge regarding adverse consequences and of the
existing knowledge from previous clinical studies of similar treatments.
Clinical investigators, who are the beneficiaries of sponsored drug trials
and resulting publications, have a conflict of interest in recruiting
patients. Independent institutional research groups could be set up to
monitor the case selection and conduct of sponsored clinical trials for
which institutions and researchers receive payment from industry.”

This statement questions the knowledge or lack of knowledge of the
subjects who participated in the natalizumab studies, the conflict of
interest of investigators involved in the study and the lack of
independent monitoring of commercially funded trials. These issues are not
unique to the clinical development of natalizumab in MS and have been
widely debated elsewhere. The economic reality is that it is very
difficult to develop any new drug without industry involvement. The
natalizumab studies were performed to the highest ethical standards in
accordance with the Declaration of Helsinki [10], the International
Conference on Harmonisation (ICH) guidelines and good clinical practice
(GCP) [11]. All subjects gave written informed consent. Subjects who
progressed during the blinded phase of the studies were informed of this,
offered licensed disease-modifying therapy according to local clinical
guidelines, and had to volunteer again by giving written informed consent
to remain in the study. The study protocols were developed by the
investigator advisory committees and sponsors and were approved by central
and local ethics committees. The studies were also overseen by independent
safety monitoring committees.

We would also like to point out two errors in Dr Matthew Grove’s
commentary on the Chaudhuri paper (dated 17 February 2006) [12]. Dr Grove
states “As a brief aside; Dr. Chaudhuri mentions that Case 1 was exposed
to both infliximab (for Crohn's disease) and Natalizumab (for MS). One
wonders whether the patients’ physicians considered whether the infliximab
might have caused or aggravated the MS.”

This case did not have MS, he received natalizumab as part of
clinical trial to evaluate the clinical efficacy of natalizumab in Crohn’s
disease. Dr Groves also states, that “in the AFFIRM trial a difference in
relapses of 0.49 per annum between the two groups equates roughly to an
NNT of 200 to prevent one relapse per annum.” His calculations are
incorrect the actual number-needed-to-treat (NNT) is 2.

In conclusion, as clinicians who look after people with MS and as
investigators with an academic research interest in MS, we strive for
equipoise; the ethical requirement of trying to balance the needs of
individuals with the need to find more effective treatments for this
devastating disease. Natalizumab has now been proven to be a more
effective therapy for the treatment of relapsing remitting MS than
existing licensed products [4,5], which is why the FDA granted it an
accelerated approval. What is required are studies to further define the
risks associated with natalizumab therapy and to try reduce or eliminate
these risks, so that people with MS and their clinicians can make an
informed decision about the most appropriate situations to use this drug.

Competing interests: All the authors have been principal
investigators in the U.K. in the “randomized placebo-controlled trial of
natalizumab for relapsing multiple sclerosis (AFFIRM STUDY)” sponsored by
Biogen-Idec and Elan Pharmaceuticals.

Dr David Barnes (David.Barnes@stgeorges.nhs.uk)

Professor David Bates (david.bates@ncl.ac.uk)

Dr Gavin Giovannoni (g.giovannoni@ion.ucl.ac.uk)

Professor Clive Hawkins (Clive.Hawkins@uhns.nhs.uk)

Dr Jackie Palace (jacqueline.palace@clinical-neurology.oxford.ac.uk)

Dr Mohammad Sharief (m.k.sharief@kcl.ac.uk)

Dr Basil Sharrack: Basil.Sharrack@sth.nhs.uk)

Dr Eli Silber (Eli.Silber@kingsch.nhs.uk)

Dr Carolyn Young (carolyn.young@thewaltoncentre.nhs.uk)

References

1. Chaudhuri A. Lessons for clinical trials from natalizumab in
multiple sclerosis. BMJ. 2006 Feb 18;332(7538):416-9.

2. Tubridy N, Behan PO, Capildeo R, et al. The effect of anti-alpha4
integrin antibody on brain lesion activity in MS. The UK Antegren Study
Group. Neurology. 1999 Aug 11;53(3):466-72.

3. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of
natalizumab for relapsing multiple sclerosis.N Engl J Med. 2003 Jan
2;348(1):15-23.

4. Rudick R, Stuart WH, Calabresi PA, et al. Natalizumab plus
interferon beta-1a for relapsing multiple sclerosis. N Engl J Med
2006;354:911-23.

5. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-
controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J
Med 2006;354:899-910.

6. Rudick R, Stuart WH, Calabresi PA, et al. Natalizumab plus
interferon beta-1a for relapsing multiple sclerosis. N Engl J Med
2006;354:911-23.

7. Youary TA, Major EO, Ryschkewitsch C, et al. Evaluation of
patients treated with natalizumab for progressive multifocal
leukoencephalopathy. N Engl J Med 2006;354:924-33.

8. Ghalie RG, Mauch E, Edan G, et al. A study of therapy-related
acute leukaemia after mitoxantrone therapy for multiple sclerosis. Mult
Scler 2002;8:441-5.

9. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-
controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J
Med 2006;354:899-910.

10. Rudick R, Stuart WH, Calabresi PA, et al. Natalizumab plus
interferon beta-1a for relapsing multiple sclerosis. N Engl J Med
2006;354:911-23.

11. World Medical Association. Declaration of Helsinki: ethical
principals for research involving human subjects. As amended in Tokyo,
2004. Ferney-Voltaire, France: The Association; 2004. Available:
www.wma.net/e/ethicsunit/helsinki.htm (accessed 27th February 2006).

12. http://www.fda.gov/cber/ich/ichguid.htm (accessed 27th February
2006).

13. Grove ML, True costs of Miracle Drugs?
http://bmj.bmjjournals.com/cgi/eletters/332/7538/416. (accessed 27th
February 2006).

Competing interests:
All the authors have been principal investigators in the U.K. in the “randomized placebo-controlled trial of natalizumab for relapsing multiple sclerosis (AFFIRM STUDY)” sponsored by Biogen-Idec and Elan Pharmaceuticals.

Competing interests: No competing interests

07 March 2006
Gavin Giovannoni
Reader in Clinical Neuroimmunology
David Barnes, David Bates, Clive Hawkins, Jackie Palace, Mohammad Sharief, Basil Sharrack, Eli Silber, Carolyn Young
Institute of Neurology, UCL, Queen Square, London WC1N 3BG