Talk:Natalizumab

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Archives
through March 2008

1 Archive
2 Stem cells
3 FDA did not withdraw Tysabri nor cancel it's License
4 the PML deaths
5 How many "real" MS patients on N (and Avonex) got PML?
6 Today's MS Society (UK) 12-page pull-out on MS in London Times
7 End of archive
8 Analysis article on the other PML death
9 MEDMOS: "compare ... with others in its class" (auto-immune)
10 Europe?
11 N allegedly leading to "liver injury" (and corrollary)
12 Remove NPOV tag?
13 Review article
14 The corrollary: - in fact "liver injury" leading to N (?)
- 14.1 break
15 Undue weight
16 MEDMOS and Wiki de-facto standard for treating the Liver issues
- 16.1 Multiple Sclerosis DMD class
- 16.2 Crohns Disease DMD class
17 The 900 other drugs that cause Liver Injury
18 FDA new safety plans on drugs and biologicals
19 Legal status
20 PML and interactions
21 Proposal for N new content/format
22 Efficacy
23 Image

[edit] Archive

I have created an archive of the old discussions. I have copied back to this page the most recent conversations, in collapsible headers on the longer posts. Free free to read and reply to these conversations if you want; any text inside the {{hide}} template will be collapsible, and any text in the section after the }} will be displayed normally. Otherwise, reading involves clicking the header, and editing involves clicking the same edit button that you'd usually use.

In case anyone needs to know in the future, I used the Move Page method. WhatamIdoing (talk) 22:29, 29 March 2008 (UTC)

[edit] Stem cells

An interesting property of natalizumab, and possibly even a therapeutic mechanism, it is ability of mobilising haematopoietic stem cells (CD34+ mononuclear population) from the bone marrow: doi:10.1182/blood-2007-10-120329 JFW | T@lk 10:46, 25 March 2008 (UTC)

I enquired today of colleagues if this had any significance, and apparently the drug will be trialled in multiple myeloma. Nothing on the clinicaltrials.gov site however.io_editor (talk) 01:50, 27 March 2008 (UTC)

[edit] FDA did not withdraw Tysabri nor cancel it's License

Reference #1 - from NEJM - withdrawal by Biogen -http://content.nejm.org/cgi/content/full/353/4/432

Reference #2 - FDA approval history - subsequent "re-approval" was actually a "supplemental" (Biological License); original License was in place - http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist ....io_editor (talk) 01:17, 29 March 2008 (UTC)

True, but the article does not claim anything to the contrary. Voluntary withdrawal = done by the manufacturer, not the FDA. WhatamIdoing (talk) 22:09, 29 March 2008 (UTC)

[edit] the PML deaths

From Io io editor

There were 3 PML cases; of which 2 died. Only in full-blown Aids is PML usually seen, and is usually fatal due to the absence of an immune system. So how did these patients die?

1. http://content.nejm.org/cgi/content/full/353/4/375?ijkey=b24b4864c7f8f2c41bcc31d8e021ff52b2f40430
2. http://content.nejm.org/cgi/content/full/353/4/369?ijkey=f3eceb18a94aa8b54237f55ba4a7286c8f4e071f
3. http://content.nejm.org/cgi/content/full/353/4/362

What all 3 had in common were 2 things:

1. con-committant drugs (avonex in 2 "MS" patients; and in the CD patient, not simultaneous but was
already chronically immuno-suppressed - had already low lymphocyte counts due to prior immuran and infliximab).
2. a bungling period 3 to 5 months of PML mis-diagnosis before death or partial recovery (in one
case of course the mis-diagnosis of a brain tumor continued for 2 years post-mortem). In this 3 to 5
months of PML mis-diagnosis, all 3 received massive amounts of powerful immuno-suppressive medications - all
for the wrong issues.

Treatment of PML in these non-Aids cases appears possible - http://archneur.ama-assn.org/cgi/content/abstract/64/2/169 - ....io_editor (talk) 01:33, 29 March 2008 (UTC)

[edit] How many "real" MS patients on N (and Avonex) got PML?

From Io io editor

By "original diagnosis", 2 is the answer; 1 died, 1 lived. However, a few months after the NEJM simultaneously published the case histories, it published a pair of letters (presumably, among many) which, to the embarrassment of the authors, cast doubt on the MS diagnosis of both patients - http://content.nejm.org/cgi/content/full/353/16/1744 - rather than explain all that, and for those who have no NEJM access, here is a full copy, minus the references -

<<<<<" To the Editor: According to the established definition of multiple sclerosis, the condition in the patient described by Kleinschmidt-DeMasters and Tyler (July 28 issue) should not have been diagnosed as multiple sclerosis. Apart from the unusual clinical findings, no oligoclonal bands were detected in two separate examinations of the cerebrospinal fluid, and repeated magnetic resonance imaging (MRI) scans obtained over the course of several years showed new and enlarging, but never enhancing, lesions. The most convincing argument against a diagnosis of multiple sclerosis is the neuropathology: no lesions that are characteristic for multiple sclerosis were detected. The patient described by Langer-Gould et al. in another article in the same issue may also raise concern about the diagnosis of at least "typical" multiple sclerosis. One to two oligoclonal bands in the cerebrospinal fluid would have to be considered negative, and repeated MRI scans would not show enhancing lesions. Therefore, it does not seem appropriate to conclude that patients with multiple sclerosis may be at risk for progressive multifocal leukoencephalopathy (PML) owing to treatment with natalizumab and interferon beta-1a. Is it possible to misdiagnose subclinical nonfatal cases of PML as multiple sclerosis in patients who are not obviously immunosuppressed? Further investigations of JC virus infections should extend our knowledge of this scenario.

Thomas Berger, M.D., M.Sc. Florian Deisenhammer, M.D., M.Sc. Innsbruck Medical University A-6020 Innsbruck, Austria

Dr. Berger reports having received unrestricted research-grant support, lecture fees, and consulting fees from Berlex, Biogen-Idec, Sanofi-Aventis, Schering, and Serono; and Dr. Deisenhammer, unrestricted research-grant support, lecture fees, and consulting fees from Biogen-Idec, Schering, and Serono.">>>>> (Io-Editors's note - this means almost all the MS DMD maker/ competition)

To the Editor: Kleinschmidt-DeMasters and Tyler described a patient with multiple sclerosis and PML that developed after she received natalizumab treatment. However, some of the findings in this patient are uncommon in multiple sclerosis. The absence of contrast enhancement in the MRI studies that were performed — almost a rule in patients with PML — is uncommon in multiple sclerosis. The lack of intrathecal synthesis of IgG is unusual in multiple sclerosis, although it is frequent in PML. Moreover, an autopsy study found no multiple sclerosis plaques but only PML lesions. Therefore, the pathological findings did not support a diagnosis of multiple sclerosis, which raises some questions. Can initial PML mimic multiple sclerosis? Was PML the only disease in this patient? To our knowledge, PML with a relapsing–remitting course has not been described. To clarify whether PML may have a relapsing–remitting course, it is necessary to study the cerebrospinal fluid in patients with relapsing neurologic disorders to rule out this disease. This seems particularly important for patients with suspected multiple sclerosis with atypical findings, such as early mental symptoms or an absence of oligoclonal bands. If it is demonstrated that PML can have an initial relapsing–remitting course, the risks of natalizumab treatment should be reevaluated.

José C. Álvarez-Cermeño, M.D. Jaime Masjuan, M.D. Luisa M. Villar, Ph.D. Hospital Ramón y Cajal 28034 Madrid, Spain

Note that these letters raise the possibility that, not only did one or both patients never had MS, but may have had "sub-clinical" PML. Perhaps in recognition of this (because the anomaly was raised at the FDA Advisory Committee Hearings - reference available), patients "who already have PML" are contra-indicated on the label for N treatment....io_editor (talk) 13:23, 29 March 2008 (UTC)

In actual practice, both in all trials and in 2 years of widespread availability, no MS patient (real or disgnosed) has contracted PML while on N alone - http://www.biogenidec.com/site/tysabri-information-center.html (by Dec '07, there were 21,000 MS patients on N)....io_editor (talk) 14:16, 29 March 2008 (UTC)

I'm posting the third letter on that page, for completeness' sake: Drs. Kleinschmidt-Demasters and Tyler reply: We appreciate the comments of Drs. Berger and Deisenhammer and Dr. Álvarez-Cermeño and colleagues. Our involvement with this case began only post mortem; we were not involved in this patient's initial clinical evaluation, diagnosis, and treatment. The clinical and laboratory data presented were supplied by the patient's treating physician and supplemented by the Biogen company representative. Unfortunately, in some instances only the original MRI reports, not the actual scans, were available for independent review.

A variety of diagnostic criteria for multiple sclerosis have been proposed, including the widely accepted criteria of McDonald et al.1 These criteria do allow for the diagnosis of multiple sclerosis to be made solely on clinical grounds in a patient with two or more attacks and objective clinical evidence of two or more lesions. Criteria specific to MRI can provide supportive evidence of the dissemination of lesions over time; this criterion can be satisfied by the appearance of new T2-weighted lesions on appropriately spaced sequential scans. Oligoclonal bands on evaluation of the cerebrospinal fluid and enhancing lesions as shown on MRI are found in the majority of patients with definite multiple sclerosis; however, their presence is not absolutely required for diagnosis, nor does their absence completely rule out a diagnosis of multiple sclerosis.

We cannot resolve whether the absence of multiple sclerosis lesions at autopsy reflects obliteration of a limited number of multiple sclerosis plaques by the widespread and extremely destructive PML lesions, sampling error, or the presence of an alternative disease process. With regard to this last possibility, we believe it is unlikely that a chronic indolent or relapsing–remitting form of PML was the sole disease that this patient had or that it was responsible for this patient's symptoms early in her clinical course.

Our report, in combination with the others published in the same issue of the Journal,2,3 clearly indicates that natalizumab is associated with an increased risk of PML in patients without other recognized risk factors for this disease. The common denominator in all three reported cases, regardless of the underlying disease, was treatment with natalizumab.2,3

We hope that ongoing studies will clarify the pathogenesis of this disorder, including the viral factors and specific host factors responsible, and also the mechanisms by which natalizumab facilitates induction of PML.

B.K. Kleinschmidt-DeMasters, M.D. Kenneth L. Tyler, M.D. University of Colorado Health Sciences Center Denver, CO 80262 - Antelan^talk 16:14, 29 March 2008 (UTC)

Their long-winded excuses, for failing to note the strange diagnosis in their single-patient paper, doesnt help ths page much - but here is part of their conclusion - "we believe it is unlikely that a chronic indolent or relapsing–remitting form of PML was the sole disease that this patient had" - all the more remarkable given that all they had was an autopsy....io_editor (talk) 16:32, 29 March 2008 (UTC)

[edit] Today's MS Society (UK) 12-page pull-out on MS in London Times

From Io io editor

[edit] End of archive

Please add new topics for discussion to the bottom of the talk page. WhatamIdoing (talk) 22:01, 29 March 2008 (UTC)

[edit] Analysis article on the other PML death

From an unimpeachable source, article analysing the other PML death (patient had life-long Crohn's Disease)...quote = "Furthermore, the treatments were, among other things, themselves linked directly with the development of PML!"....io_editor (talk) 01:40, 2 April 2008 (UTC)

From that article, which is from 2005: we are not doctors and so our opinion is purely non-medical. What's more, that site is run anonymously; not exactly an unimpeachable attribute. Antelan^talk 01:49, 2 April 2008 (UTC)

Yesterday you described the UK MS Society as an "robust and respected institution". Do you know much about either? Suggest ask some MS patients; this is one of the primary USA sites they use. And - what about the content of the article? Does it skew the NEJM facts? Time to "return to Science" here?...io_editor (talk) 02:28, 2 April 2008 (UTC)

As I have said, the MS Society is a robust and respected institution. This is just an anonymous website run by people who are admittedly not medical professionals. I happen to evaluate the quality of a source based on more criteria than simply "agrees with my position." Antelan^talk 03:47, 2 April 2008 (UTC)

It is run by people who know a lot about MS; it is part of their life, their biggest issue. What do you know about MS ? Despite all your posts here, do you realise that nowhere have you discussed any of the medical science presented on the wiki or this talk page?io_editor (talk) 13:24, 2 April 2008 (UTC)

This is only because there have been many procedural issues brought up here, taking up time that could otherwise be devoted to article building. If you had more carefully focused your concerns to those that pertain to this subject (for example, if you would have placed the list of other articles that need to be updated in a more appropriate place), some of these "nonmedical" posts of mine wouldn't have been necessary. Antelan^talk 23:03, 2 April 2008 (UTC)

This is section is not "procedural", it is "science"-based. Seriously, how can you police someone who knows a lot about MS, when you know so little about it?....io_editor (talk) 00:06, 3 April 2008 (UTC)

After the Essjay controversy, purported "credentials" on Wikipedia have lost value. And I don't recall having discussed with you my knowledge on this subject. In fact, I distinctly recall your refusal to discuss it multiple times. Therefore, I'll expect you to stop with ad hominem innuendo. Antelan^talk 02:14, 3 April 2008 (UTC)

[edit] MEDMOS: "compare ... with others in its class" (auto-immune)

In MEDMOS WP guides how Drug pages be written - "For example, a long list of side effects is largely useless without some idea of which are common or serious. It can be illuminating to compare the drug with others in its class...." Last week I listed the DMD drugs in MS, Crohns and those implicated in [PML], and found no comparables close to this N page. Now its time to look at the other wiki-listed autoimmune disease DMD-class drugs. I used the shorter list on the autoimmune disease page; the longer list is very long with very rare conditions, some not treatable, and I doubt it would have a different result anyway. Accordingly:

coeliac disease - "steroids or immunosuppressants (such as azathioprine)" for refractory disease - azathioprine is the human carcinogen described before, being replaced by better drugs due to inherent dangers - but nothing in lead.

diabetes mellitus type 1 - insulin - further comment not needed.

systemic lupus erythematosus ("lupus") - "treatment is restricted to dealing with the symptoms" - which include DMARDS (see previous comparisons)

Sjögren's syndrome - 3 drugs to treat symptoms, including Cyclosporin - risky drug but AEs lower down on Wiki.

Hashimoto's thyroiditis- thyroid hormone replacement - further comment not needed.

Graves' disease - radioiodine which is radioactive - dangers are down the Wiki page.

idiopathic thrombocytopenic purpura - prednisone - and intravenous immunoglobulin - side effects including aseptic meningitis, acute renal failure and pulmonary edema are all down the page, just a list.

rheumatoid arthritis - a dozen drugs, some quite dangerous and some on the PML causative list - none (I checked every one) however deal with AEs in lead or in-depth.

Conclusion: on Wiki, the wp:weight of PML and death on the N page is hard to equal in comparable DMD drugs....io_editor (talk) 02:22, 2 April 2008 (UTC)

This has already been discussed. This is the wrong place to suggest improving other articles. Consider WP:MED. Antelan^talk 03:51, 2 April 2008 (UTC)

The issue is not the rarity of the side effects of PML, it's that they caused the drug to be pulled from the market, then re-instated. The 'in and out and in' of N as an approved drug is completely independent of specifics of the side effects. The adverse effects (such as specifically PML) should be, and are, discussed separate from the circumstances of the approval-withdrawal-reapproval. The only reason PML is linked is because it would be odd to say the drug was pulled form the market without saying why. Wikipedia is not a drug manual, it's an informative encyclopedia, meaning it contains more than just raw medical data, it has information about how the drug has affected and been affected by real life, including approval by sanctioning bodies. PML is more than just a side effect, it is a notable factor in the 'medico-political life' of the product. The process by which the drug was released onto the market is what is notable, not the specifics of why. The whole section of legal status is a totally separate and interesting aspect of the history of natalizumab, unrelated to PML except for PML being the factor causing the withdrawal of the drug. In that section the focus is, or should be, on the history of regulation of natalizumab, and not on the 'why'. By focusing on on PML as just a side effect, and a very rare side effect, you are missing the reason why PML is mentioned in the lead and why it is discussed in more than just in the side effects section. PML is a minor bit of context in the drama that is the process by which natalizumab reached and was removed from, then again reached the market. WLU (talk) 17:48, 2 April 2008 (UTC)

"The focus is, or should be, on the history of regulation...." If I had to go through the list of Comparables for the same criteria you advocate, what do you think will be found? One, Two, Three Comnparables?..........The page first and forenmost should be what it is, or what "you-mean-by-IS-is" - as a great man once spoke - not to be dominated by the stir-in-the-media-drama that happened 3 years ago....io_editor (talk) 18:31, 2 April 2008 (UTC)

I'm not bothering to go through the list because I think the other pages are irrelevant. The page is first and foremost about natalizumab. And that includes everything that possibly can relate to natalizumab, not just drug info. The majority of the page is about the drug's clinical uses, properties and affects with one section that discusses a very notable aspect of its history. Honestly, I don't know what you want. Perhaps you could write up a sub page that represents your ideal natalizumab article and show it to me/us. We can then see how it would be different from the present one. And thank you for comparing me to my favourite President. I've adjusted my comment above to try to be more clear - the approve-withdraw-reapprove process I was talking about was specific to a single section, legal status, but the lead should summarize the whole article as best possible, including the legal section. WLU (talk) 20:25, 2 April 2008 (UTC)

I did not compare people - that's just what the great man said. My sub-page would look like infliximab or rituximab which are well-done, multi-indication, serious+fatal_AE comparables (I remember the interferon pages are weak, but maybe one or other is OK). As you well know, I dont agree with your last sentence, nor know of a wiki-comparable-DMD....io_editor (talk) 00:19, 3 April 2008 (UTC)

When you're writing a medical article, yes it's for everyone, but how can you not think of that particular sub-set of readers whose very lives it might affect - going on, or switching to, a DMD is a HUGE decision/gamble/life-style-change - including for example the need for a little clinical trial in itself for the patient, by that I mean taking a base-line MRI to see later if it works specifically in her/his case; or works better than the older drugs; the "risks" must be balanced by the risks (prognosis : physical & cognitive) of not taking a stronger drug; they don't know if, just because they had a recent relapse whether this means they are getting worse or whether they should be now OK for another 6-12 months - OK, enough, for them it is a defining moment...io_editor (talk) 00:26, 3 April 2008 (UTC)

Good, if you already have a model, go write up a sub-page. Also, we are an encyclopedia, not doctors. We do the best we can but are very, very far from perfect. WLU (talk) 11:43, 3 April 2008 (UTC)

This list is irrelevant. This is a product article, not a disease article. If you want to compare Multiple sclerosis to Coeliac disease, then that's fine -- but please do that at the MS article, not here. WhatamIdoing (talk) 22:41, 2 April 2008 (UTC)

Nonsense. Nowhere did I compare diseases, nor speak to their relative differences, nor how their Wiki pages look different or the same...io_editor (talk) 00:00, 3 April 2008 (UTC)

And you found zero drugs for any of these eight diseases that had been removed from and then returned to the market. But you still insist that this article should match the articles for drugs which have non-comparable histories. Can we be done with this discussion now? You are never going to change my mind about the historical, legal, regulatory, and economic importance of this issue.

Note, please:

I refuse to remove blackbox warnings from the Adverse effects section, on this or any other drug article.
I refuse to remove critical information about drug-drug interactions from the Interactions section.
I refuse to remove the withdrawal and re-marketing from the Legal status section.
And YES, when something legitimately belongs to three of the five sections in the article -- when one complicated situation basically is three of the five sections -- it belongs in the lead.

I'm sorry that you don't like it, but you're not changing my mind. If you want to de-emphasize it, then I suggest you get to work expanding the other parts of this article instead of making lists of drug and disease pages that are missing critical information. Perhaps, for example, you would like to expand the more important adverse effect for patients, which is liver damage. WhatamIdoing (talk) 00:19, 3 April 2008 (UTC)

You dont have to refuse things I did not ask of you. What do you mean by "the more important adverse effect for patients, which is liver damage"?...io_editor (talk) 00:34, 3 April 2008 (UTC)

I mean "the potentially deadly adverse effect that is much more likely to happen to real patients, and that all regulatory agencies and the pharmaceutical companies agree is caused by natalizumab." Doesn't a real risk of dying or needing a liver transplant seem important? It's mentioned in the article, but it would be nice to have more information, like whether this risk is "small" or "very small," or whether it is reversible.

So you just proved you know nothing, not only about N, but about MS itself. I have not time for on-line "School" today.io_editor (talk) 20:55, 3 April 2008 (UTC)

You have spent weeks trying to get one or more of the four mentions of the regulatory history and warnings removed. Sorry: you're stuck with all four of them, for the four reasons I gave above. However, the addition of information about other adverse effects, or the drug's effectiveness, or the registered patient program, or anything else would help balance the PML info. If you want to have a "balanced" article, you need to do it by adding information instead of demanding removal. WhatamIdoing (talk) 01:50, 3 April 2008 (UTC)

Just wanted to drop a note to say that WhatamIdoing's refusals above are backed by the spirit of an encyclopedia, and the policies of this encyclopedia in particular. Antelan^talk 00:28, 3 April 2008 (UTC)

The spirit of journalism.io_editor (talk) 20:55, 3 April 2008 (UTC)

All for are exactly the reason I think the page adequately deals with the PML information and don't see a pressing need to expand or remove any info to date. WLU (talk) 11:43, 3 April 2008 (UTC)

[edit] Europe?

I've been looking for citations to justify the 'approved in Europe' aspect of natalizumab, and the two I've come up with seem to support that it is not approved for use in Europe (possibly just for Crohn's disease - I think it's approved for use with MS). I'm not a drug wonk, so I'm not sure what all the terminology actually means. The two cites I've found are [1] and [2], but I've only scanned and they may just imply that they're not for use with Crohn's disease. Io, could you link to the European Union's approval? Is there a better, second or more lay-summary of it's approval for use in Europe (i.e. a news release from EU medical agencies that state what it's indicated/contraindicated for)? I'll do the citation template if you'd like. I was surprised to see that it wasn't sourced on the main page, and have been trying to track it down. WLU (talk) 18:10, 2 April 2008 (UTC)

It is not approved for Crohns in EU. If you go to MS wiki, or Treatment-of, you will see the EMEA label (MS) somehwere....io_editor (talk) 18:21, 2 April 2008 (UTC)

OK, thanks for confirming. I've added cites and statements to this effect on the main page - have a look 'cause I'm prone to mistakes. WLU (talk) 18:25, 2 April 2008 (UTC)

It's complicated: a prescription medication must be approved to be legal for sale. However, that's separate from the drug being indicated for the treatment of any given disease. Indications can be regulatory (eg, the US FDA reviewed your paperwork and agrees with you) or scientific (nobody filed the paperwork, but everyone agrees that it works).

As it happens, in the US, you can't get approval without at least one indication. However, once a drug is approved, it can be prescribed off-label for any patient, with any condition, according to the physician's judgment. So you can be given an anti-seizure drug for chronic pain, and no one minds.

Whether or not the paying agency will agree to pay for it is an entirely separate issue. So you could have a drug that is approved for legal sale in the UK, indicated for Crohn's according to the scientific literature, and rejected by the NHS as too costly compared to the expected benefits. WhatamIdoing (talk) 19:42, 2 April 2008 (UTC)

I must agree that these paragraphs are very accurate assessments. In an interesting wrinkle, all other DMDs were rejected in the UK by the NHS/NICE, but following an outcry, they were made available under a "risk-sharing-scheme" - should the drugs not prove to have certain limits of efficacy (which they will probably meet, unless the standards are high) then the pharmas will have to refund the NHS back....io_editor (talk) 00:10, 3 April 2008 (UTC)

Can I ask the favour of a review of my recent edits to see if they are correct? Reading this stuff and trying to edit is like trying to solve the chinese room problem. WLU (talk) 20:19, 2 April 2008 (UTC)

Do you know what you are doing here?. And why did you do it?....io_editor (talk) 00:44, 3 April 2008 (UTC)

It was fine. I added a few more details just for fun. WhatamIdoing (talk) 22:37, 2 April 2008 (UTC)

I went to look at WLU's edits in reverse order and have come to here. The use of "suggested" to replace "demonstrated" is, as you almost certainly know, clearly wrong (and do I have to explain this?)...io_editor (talk) 00:44, 3 April 2008 (UTC)

I agree with your interpretation of the studies as demonstrating rather than suggesting. However, this could be stated less confrontationally, for what it's worth. Antelan^talk 01:18, 3 April 2008 (UTC)

<undent>The reason I placed the word 'suggested' rather than 'demonstrated' is because of the non-approval in Europe. In one of the citations I placed I remember one of the reasons for non-approval for CD was because the reviewers felt it was not adequately demonstrated as effective against CD. I'll try to track it down later today. Of course, you could have assumed I had a reason and asked politely, since I don't believe I have ever edited the page without a good reason. But whatever. Keep pitching them, I'll keep knocking them out of the park. Thanks to WhatamIdoing and Antelan for proofreading and correcting my contributions. WLU (talk) 11:38, 3 April 2008 (UTC)

You "will track down" a reason and only then "hit it out of the park". Unless you know something about Crohns, you will not understand, and I have no time for School today. Also, your edit description omitted this fundamental demotion. Dont know if reverted, but perhaps you are comfortable mis-leading those to whom it may be relevant.io_editor (talk) 21:03, 3 April 2008 (UTC)

Ioio, you need to stop insulting other editors here personally. This doesn't help anyone improve anything. Antelan^talk 22:49, 3 April 2008 (UTC)

I insulted no-one. At least WLU has come out to me in the past that he knows next-to-nothing about this area of medicine. In your case, I had to accuse. What is more, the last 6 sections on this Talk page I had started with Science-based and/or MEDMOS-directed comparisons. Because you are unwilling or unable to provide Scientific input - and nowhere have you done so - the converstaion degenerates....io_editor (talk) 22:25, 4 April 2008 (UTC)

Not to mention blockable if it continues long enough. Anyway, in this one, in the Benefit/risk assessment section it discusses the benefit/risk ratio. I was wrong about the effectiveness, the reason for non-approval was due to the R/B ratio, so I've corrected it accordingly. WLU (talk) 10:43, 4 April 2008 (UTC)

The links to the 3 trials were in the same paragraph.io_editor (talk) 22:25, 4 April 2008 (UTC)

The funny thing is, despite knowing nothing of natalizumab two months ago, I believe I've done more to expand and wikify the page than just about anyone. You're welcome, now the page looks credible to other wikipedians and the general reader, as well as being better referenced and more accurate. I'm great, I might just give myself a barnstar. Yay for me! My ignorance is obviously not a barrier to greatly improving pages. Citizendium, the expert-only editable encyclopedia, doesn't have an entry. If you really wanted to, you could copy the GFDL-content here over to Citizendium and start the page though. Ignorance is not a barrier to good work. WLU (talk) 23:19, 4 April 2008 (UTC)

But this - despite the 3 cites and FDA approval - clearly exposes your goal. My edits show, and the edits of others in Jan/Feb were towards reaching a balanced page with nothing hidden or skewed.io_editor (talk) 15:52, 5 April 2008 (UTC)

Or, rather than an extremely nefarious plan easily foiled by checking the source, something I always do when I suspect an error was made, I simply made a mistake and corrected it here. And I did ask people to check my work, it could have easily been fixed. But please, feel free to give me further occasion to correct your misapprehension. WLU (talk) 18:24, 5 April 2008 (UTC)

[edit] N allegedly leading to "liver injury" (and corrollary)

Once again, starting what I hope will be a Science (only?) based section, and prompted by the edit here in which WhatamIdoing asks "to expand the more important adverse effect for patients, which is liver damage" and then here where he means "the potentially deadly adverse effect that is much more likely to happen to real patients, and that all regulatory agencies and the pharmaceutical companies agree is caused by natalizumab." Supported by concensus (Antelan, WLU), but it is completely wrong.

In looking at AEs from page 8 to page 12 of the FDA label there are 3 tables, covering a total of 4 Phase III trials, listing AEs (not even limited to SAEs) where frequency in N exceeded placebo by just ONE percent (1%).
Although the lists are long, liver (hepatic) injuries, or raised enzyme levels, appear in NONE of these tables. With so many patients (3,000+) in the trials, this is clinical proof that in fact liver issues are highly unlikely to occur at all.
Furthermore, "all regulatory agencies and the pharmaceutical companies" do not "agree it is caused by N". Instead what the "Dear Doctor" letter says is that "clinically significant liver injury has been reported in patients treated with TYSABRI in the postmarketing setting". It refers only to reports by individual doctors on a handful of individual patients (out of 20,000+) in ordinary use, not clinically supervised or vetted, and without regard as to who these doctors are, or what other conditions these patients had, or what other drugs they had been taking. Neither the drug companies nor the FDA are in a position to review such cases, nor their causes. Once a report is duplicated a number of times, all the drug companies can do is write the letter, and the FDA publishes.
Finally, all such "injuries" were reversed fully after N withdrawal.io_editor (talk) 18:08, 5 April 2008 (UTC)

You're right, in part: this adverse effect wasn't apparent in the original clinical trials. In fact, in the original clinical trials, natalizumab had fewer problems with liver damage than the controls. However, since then, they've documented hepatotoxicity that appears with the drug, disappears when you remove the drug, and reappears when you reintroduce the drug. Nobody (except perhaps yourself) disagrees with this.

I've added the information, with a large number of sources. The only thing I couldn't find was a reliable source that states that the liver damage is always reversible. WhatamIdoing (talk) 23:05, 5 April 2008 (UTC)

You're right, nobody here would disagree with you, because they share the same goal, which is wp:undue. The fact is that instead of "they've documented hepatotoxicity" in fact they have NOT documented hepatotoxicity, because as I wrote above these are not clinical trial results, but independent doctor reports, which is perfectly clear from the cite. Furthermore they are on patients with individual characteristics, which quite possibly (if you knew MS beyond Wiki) included prior liver damage.io_editor (talk) 15:15, 6 April 2008 (UTC)

There's what, 6 sources documenting liver toxicity? And the FDA, Elan and Biogen all agree that Tysabri can cause liver damage? I'd say it's verifiable that it causes liver toxicity and your analysis consists of original research which bears no weight. Mwhahahahah, the plot continues aided by wikipedia's patsies in drug companies and the FDA. Dance puppets, dance! WLU (talk) 19:46, 6 April 2008 (UTC)

All your statements are false. I referenced the clinical trial results; you reference non-clinical, sporadic reports. See wp:MEDMOS for what counts...io_editor (talk) 20:41, 6 April 2008 (UTC)

No, you interpreted the clinical trial results and came to a conclusion. I referenced the sources which are summarized in the text and all agree that the liver problems are something worth noting. Do you have any source where the source says liver toxicity is not a concern? If you provide a source and a quote of an unequivocal statement so I can search for the quote, then it can certainly be included in the page as long as its a reliable source. To avoid WP:OR, the source must make the claim, not an editor. WLU (talk) 22:45, 6 April 2008 (UTC)

Clinical evidence in thousands was ZERO - not interpretation, but fact. Statistically remarkable (even "odd") it could not make the 1% differential that in 4 separate trials. The multiple sources cited are just massive wp:undue to boost the paragraph size. One statement there you already know is outright lie. Consistent.io_editor (talk) 19:03, 7 April 2008 (UTC)

This is an issue that should be taken up with the FDA. Until then, and unless something comes out that casts serious doubt on the FDA's own claims, I don't see how this information could reasonably be removed from this article. Antelan^talk 00:35, 7 April 2008 (UTC)

The FDA does not make claims.io_editor (talk) 19:03, 7 April 2008 (UTC)

Semantics; they require the drug producer to produce black-box warnings, etc. Antelan^talk 20:38, 7 April 2008 (UTC)

Liver issue not even in the black-box warning. io_editor (talk) 23:02, 7 April 2008 (UTC)

I sure hope not. It's certainly mentioned on the label, as you no doubt have read. I'm sure the FDA had nothing at all to do with that... Antelan^talk 23:33, 7 April 2008 (UTC)

Of course its on label, in its proper place. Zero clinical evidence. Post-marketting "reports" only. But on this Wiki, like PML, expanded to wp:undue => your goal.io_editor (talk) 01:48, 8 April 2008 (UTC)

I consider your statement "wp:undue => your goal" to be a personal attack. You and I disagree about the role that postmarketing should play in pharmaceuticals. Fine. However, that does not warrant a personal attack. This is your final warning. Antelan^talk 03:12, 8 April 2008 (UTC)

Au contraire, your continuing wp:COI charge is a more obvious personal attack because the evidence (my edit history - go back to where I left the page in January, for 5 weeks) proves the opposite is true. io_editor (talk)

(Undent) Io-io editor, it's WP:PROVEIT time, not "insult the other editors" time. If you want to challenge the inclusion of the hepatotoxicity info, then bring us a reliable source that actually says there's no liver toxicity. I found one that says that the liver toxicity is no worse than any other drug, so that information has been included. If you want to say that it doesn't happen at all, then you need to provide a reliable source that states exactly that in plain, unambiguous language. And finally, if no such reliable source exists, then you need to make your own peace with that situation, by which I mean quit hassling everyone else for including verifiable information. If further research proves you right eventually, then I give you permission to say "I told you so" at that time (but not before then). Between now and then, please consider reading the WP:CIVIL policy. WhatamIdoing (talk) 06:46, 8 April 2008 (UTC)

Where did I say to remove ALL mention of liver mention to you or to anyone? But you found a worthless sourse and now you have a false statement on the page which is easy to dis-prove. Maybe you yourself dont know it? (hint = corollary). If needed I will explain tomorrow, out of time now.io_editor (talk) 01:55, 9 April 2008 (UTC)

Oh, a point of fact: postmarket reports are clinical evidence. I'm sure you mean to say that postmarket reports are not controlled trials. Those two terms should not ever be used interchangeably. WhatamIdoing (talk) 06:48, 8 April 2008 (UTC)

Maybe its clinical evidence for individual doctors treating individual patients. But useless to confirm cause because it is ad-hoc, unsupervised. In any case it is trumped hugely by the trials, 4 (in fact 5 if you include MS#2) and 3,000-4,000 patients. Of course in the realm of safety, it is "safety first", and the report outcomes are routinely added to the label, something that happens every day except weekends to some drug or other. You have expanded the paragraph way out of proportion to it's relevance.io_editor (talk) 01:55, 9 April 2008 (UTC)

And your reliable source is what again? WhatamIdoing (talk) 18:25, 9 April 2008 (UTC)

Well, I wrote 5 sentences, so I dont know what you mean. I presume you mean my assertion of a false statement on Liver issue - yep its still there, rather glaring after one week on the page, and I gave you 2 hints. I will cover it in a new talk section header later....io_editor (talk) 22:31, 11 April 2008 (UTC)

I haven't had time to catch up on all the reading here. I am at the point right now researching this medication and all the pros and cons that go with it. I just read about it in [3]. So far this is the only place I have been to learn about this drug. Personally I think all possible adverse events that have been documented should be mentioned in the article. This looks like a fairly new medication so things with this medication will probably change over time and more usage. I know that from a personal prospective, I am interested in all the good and the bad in a medicine so that an educated decision can be made about whether to use the drug or not. Just so other editors know, I am a patient with no medical training what so ever. Thanks for listening, --CrohnieGal^Talk 19:03, 9 April 2008 (UTC)

Hi Crohnie, I have seen your User page, and your interest is only natural. The issue is not one of "mention" in the article, it is one of rather heavy wp:weight - for example, compare the other biologics for Crohns (I did, on this Talk Page, but it got Archived then) with this Wiki. Of course one of the CD drugs is Adalimumab which I wrote most of anyway. But Remicade is a classic, and it is a fine page, in my opinion.io_editor (talk) 22:31, 11 April 2008 (UTC)

(undent)WhatamIdoing made his comment, Io, because without a reliable source there is no reason to adjust the page based on your comments. Seeking a reliable source is the next step when there is uncertainty or disagreement about a potential edit as mere assertions are not sufficient to support a contested edit. If you have an issue in the archive which you do not think was addressed, feel free to pull it out - archives only means the page is long, not that the issue is dead. Though if it's the undue weight placed on liver damage or PML, there's not much point. Crohnie, it's not necessary to read through the entire archive, WP:BDR means even if you make an edit we do not agree with, we can always revert and discuss. WLU (talk) 22:39, 11 April 2008 (UTC)

OK, so jump down 3 sections, time for the Corollary. But it just shows, you guys are nowhere close to MS or MS treatment, you cannot "grasp" it. If everyone could, then Neurologists would not 6 years of Med-School, 3 years as Interns, 2 or 4 years getting their feet wet....etc....io_editor (talk) 23:22, 11 April 2008 (UTC)

[edit] Remove NPOV tag?

Thoughts on removing the NPOV tag? I just read the article from beginning to end, and given the level of citation, which verifies almost all of the text (one {{cn}} referring to liver damage), I think that the page is neutral enough. Natalizumab is portrayed as an effective drug in the treatment of two diseases, with side effects and interactions that are recognized by the FDA, the EMEA and the drug's manufacturer. To date, User:Io io editor is the only person who feels the page has a neutrality problem. I, User:WhatamIdoing and User:Antelan seem convinced the page is NPOV, while some of the past editors (User:Fvasconcellos, User:MastCell, User:EdJohnston) were faced with the same issue I believe, and didn't see a problem. Can we remove the tag, or is a post on Wikipedia:Neutral point of view/Noticeboard warranted as the last place to bury the issue? WLU (talk) 15:36, 9 April 2008 (UTC)

Though I feel it's wasting their time, io_io clearly has enough of a problem with the page that it merits getting outside input rather than having one of us remove the tag, imho. Let's ask the noticeboard. Do you want to do it, or should I? Antelan^talk 20:54, 9 April 2008 (UTC)

I can, but would prefer not to. Would you mind? WLU (talk) 22:45, 9 April 2008 (UTC)

Sure thing. I've done so here. Hopefully, being terse there will avoid poisoning the well for or against any given "side". Antelan^talk 23:07, 9 April 2008 (UTC)

Works for me, thanks. WLU (talk) 23:10, 9 April 2008 (UTC)

I'm in agreement that this is a neutral article. OrangeMarlin ^{Talk• Contributions} 01:25, 10 April 2008 (UTC)

Since there's been a posting at NPOV noticeboard, I'm in favour of letting those fine people decide (or at least provide input). They're going to be more neutral, and I think we're all pretty bound up with opinions right now. WLU (talk) 01:30, 10 April 2008 (UTC)

With six days and no interest, and no reason seen by any editors to retain the NPOV tag, I am removing it. WLU (talk) 14:23, 15 April 2008 (UTC)

[edit] Review article

Review article I found trolling through the archives. pmid = 17122725 WLU (talk) 15:50, 10 April 2008 (UTC)

Is there something that you want to discuss about it? I ask not because you do not provide a link, but because I want to start a new section, and we should discuss any idea you may think is important.io_editor (talk) 22:31, 11 April 2008 (UTC)

No, I added it so someone could add it to the page, as WhatamIdoing did. I didn't have the time when I initially found it. Incidentally, if you go to www.pubmed.org, you can plug in any pubmed number to find the article it is attached to - that's why I posed just the pmid. WLU (talk) 22:34, 11 April 2008 (UTC)

Wow, fast answer. Well I looked at it. How does such a casual overview add anything, given that the 3 actual case-histories are already referenced? Perhaps it would be less intimidating to an MS patient if the 3 individual case-history references (NEJM) were removed. I challenge you to find another Wiki Medicine Page where, for a linked AE, every case that ever happened has it's history referenced as an individual paper (!!!!!) ! This is gross wp:weight on Natalizumab....io_editor (talk) 22:45, 11 April 2008 (UTC)

You are welcome, I check my watchlist frequently. It's not a casual overview, it's a pubmed journal, the near ideal source for this sort of page. And the prominence of the adverse events have been discussed to death. And the point isn't to be intimidating or not to readers, it is to inform. Other new, possibly treatment-revolutionizing drugs that have had such an unusual history would probably be discussed in such detail. Articles are based on sources. There's lots of sources. Lots of them discuss PML. There was a vivid, lengthy debate in a variety of medical journals, and the page reflects this. And if no-one is publishing concerns like yours in the pubmed journals, then it may be that even the doctors and patients who are most intimately involved with MS and CD treatment don't feel the restrictions are particularly horrific. You can always look for a WP:RFC if you'd like. WLU (talk) 22:55, 11 April 2008 (UTC)

I had italicised my main point, why not discuss seeing as you are in the mood for writing: I challenge you to find another Wiki Medicine Page where, for a linked AE, every case that ever happened has it's history referenced as an individual paper (!!!!!) ! This is gross wp:weight on Natalizumab - even before this new paper, and all the other PML papers- how many are there now?....io_editor (talk) 23:22, 11 April 2008 (UTC)

(undent)Other pages do not matter so I won't bother. Which policy or guideline do you think is violated? Certainly not WP:UNDUE. UNDUE is meant to discount parts of articles which do not represent the mainstream, either because sources that support the section are unreliable, or they represent a minority position. PML is discussed by no less than seventeen references out of thirty nine, all either pubmed journals, the most reliable of sources, publications by a major regulating agency or the manufacturer themselves. The view that PML is a large part of the history of natalizumab is obviously the mainstream. PML and natalizumab is the majority position, according to extant references. If it's not, produce a source. Any other policies you think are violated? Does everyone else think that we should seek a WP:RFC on either Io's ongoing conduct or the issue of PML? Your ongoing tendentious editing is aggravating and unproductive. You seem to think that we are the problem, despite having much more experience on wikipedia and absolutely no other editors seeing the merits of your positon. I'm willing to put up with a lot crap because of your knowledge base, but your complete failure to grasp wikiquette, good faith and civility, as well as your continued accusations against me is really, really aggravating. WLU (talk) 00:39, 12 April 2008 (UTC)

Other pages DO matter, because MEDMOS/Drugs# says to COMPARE with similars in class. Talking about different things, so I will stick to the Science.io_editor (talk) 02:20, 12 April 2008 (UTC)

Only if you take the MEDMOS quote entirely out of context, since that entire paragraph is about the importance of providing more information in drug articles. WhatamIdoing (talk) 04:33, 12 April 2008 (UTC)

Indeed, it says 'it can be illuminating to compare', not 'all drugs must be exactly the same'. And the side effects in the form of liver damage and PML are far from a generic throw-away list. It's a lengthy discussion of an area that has received considerable attention (PML) and a new side effect unknown before, that has also received a fair amount of attention (liver damage). This isn't the "... long list of side effects [that] is largely useless without some idea of which are common or serious." WLU (talk) 11:23, 12 April 2008 (UTC)

That "fair amount of attention" = largely Media attention - the links to which you have posted generously.io_editor (talk) 02:06, 14 April 2008 (UTC)

Media attention? Which of the references is to a newspaper, on-line news source or other 'media'? There are some links which are sources of medical news, but those hardly count as 'media attention' particularly given they are generally discussing news releases made by the FDA, EMEA or Elan/Biogen. WLU (talk) 16:42, 14 April 2008 (UTC)

[edit] The corrollary: - in fact "liver injury" leading to N (?)

I had intended to describe the corrollary earlier; did not get to it. On the N page the recent "Liver-scare" edits include these very flawed lines among others:

Liver damage occurs in about 1 in 1,000 (0.1%), which may be similar to other immune-suppressing drugs used to treat MS (ref this). At least 29 cases are known (ref this). The liver damage appears to be reversible.^{[citation needed]}

Putting aside the last sentence (odd, no serious outcomes reported) and the almost unprecedented standard for medical references on WikiPedia, I want to focus on the false statement that the incidence may be similar to other "immune-suppressing drugs used to treat MS". Those drugs consist almost entirely of the interferons. Yet, on the top of page 8 of the label you can read that in just 48 weeks hepatic function disorders occurred in 18% of Rebif and 10% of Avonex patients. Compare this to the natalizumab controlled trials, running out almost 3 times the duration - it was far, far less frequent.

And we had this summary before - addressing very serious Liver damage requiring transplantions in both Avonex & Rebif, something that has never happened to natalizumab. All of the above is clearly more wp:weight.io_editor (talk) 00:25, 12 April 2008 (UTC)

We represent sources, we don't compare them or make them up. If the Gross source says 'similar to other IS drugs, we would need to discount the source as unreliable, or provide a countering source. But again, we can't make it up. Though, if every other editor on the page agrees that you have a point, WP:CONSENSUS would allow re-wording. Of course, in most cases that requires being able to convince other editors that you can be trusted and are reasonable. Another great reason to assume good faith, be civil and not be a dick.

Though I do think the {{cn}} for the non-permanent liver damage is unneeded based on what I recall of sources. I may review. WLU (talk) 00:47, 12 April 2008 (UTC)

You write: "If the Gross source says similar to other MS drugs" but in fact the Gross source is clearly a casual healthcentral.com article, totally below WikiMed standards. Plus it doesn't even say what you claim it says. The numbers on the FDA labels are black-and-white for the MS drugs - the comparison made on the Wiki page is contrived.io_editor (talk) 02:20, 12 April 2008 (UTC)

Just give us a reliable source that says natalizumab does not cause liver damage, or that it causes less liver damage than other drugs. That's all we need here: something reasonably reliable that actually makes your claim. If it's true, then I'm sure you'll have no trouble at all finding a source. Until then, please don't bother complaining about this. WhatamIdoing (talk) 04:43, 12 April 2008 (UTC)

Ditto WhatamIdoing. Disputes are best resolved with sources. WLU (talk) 11:17, 12 April 2008 (UTC)

I already gave you more than "a reliable source that says natalizumab ... causes less liver damage than other MS drugs" the FDA labels themselves. Are you calling for a comparator study of your highly original claim?io_editor (talk) 02:06, 14 April 2008 (UTC)

I spent part of yesterday and then this morning looking for information about natalizumab. I came across a lot of information though I need to do even more research about this. Here is what I have found so far, which is on my sandbox attached to my user page at; [4]. I first looked up the list that Io mentions above which I found in archive 1, thus the title which I should probably change. ;) I then found the list of ten meds removed from market which both posts I found interesting.

Here are two links that give adverse reactions from natalizumab;

http://www.fda.gov/cder/Offices/ODS/MG/natalizumabMG.pdf Natalizumab/Tysabri has not been tested for use for over 2 years.
It is not known if patients over 65 have a different response.
Tysabri has not been studied for use in patients with progressive MS or in children.

Other serious allergic reactions along with multifocal leukingephnalopathy (PML) include but are not limited to; hives, itching, trouble breathing, chest pains, dizziness, chills, rash, nausea, flushing of the skin, low blood pressure. Allergic reactions usually happen 2 hours from the start of the infusion but can happen anytime.

Other side effects;headaches, urinary tract infections, lung infections, pain in arms and legs, vaginitis, feeling tired, joint pain, depression,diarrhea, rash, and stomach pain. And this one;

http://www.fda.gov/medwatch/safety/2008/Tysabri_dhcp_letter.pdf reported liver injury

Hepatotoxic-signs of liver injury including marked elevated serum hepatic enzymes and elevated total bilirubin has occurred as early 6 days of the first dosing and even after multiple dosing.

After reintroducing natalizumab, the liver injury returned providing evidence that Tysabri (natalizumab) caused the liver injury. The combination of transaminase elevation and elevated bilirubin without evidence of a blockage is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant. Patients should discontinue if signs of jaundice and/or laboratory test show problems occurring.

In closing here I am of the opinion that all severe side effects be put in the article including the information about liver injury. Thank you for your time and I hope this helps. --CrohnieGal^Talk 22:53, 12 April 2008 (UTC)

Hi Crohnie, please understand that the argument is not about whether it should get a mention - I agree it should, like other drug pages. But a "severe" problem it is NOT. Take a look at (AEs) - pages 8 to 12 of the FDA label - there are 3 tables, and in none of the 4 Phase III trials (actually 3 of these are CD trials!), did any liver (hepatic) issue frequency exceed that of the sugar pill patients. Instead the "Dear Doctor" letter says this happened only in the postmarketing setting" -reported by individual doctors on individual patients (out of 20,000+) in ordinary use, not clinically supervised nor vetted. These conditions are easy to spot and no patient got harmed; indeed those affected are probably still on N (what else is there?).io_editor (talk) 02:06, 14 April 2008 (UTC)

For otherwise unaware editors, postmarketing is also known as Phase IV clinical trials (i.e., the analysis that occurs after Phase III trials and approval for sale). Io_io has a point in that these are not randomized controlled trials; however, the subtext of his comment (ordinary use, not clinically supervised nor vetted) is that we should not rely on this information. I don't care to argue over "truth", but I do care to inform other editors that this is the absolute standard of safety analysis in the United States for every drug. Antelan^talk 06:35, 14 April 2008 (UTC)

Your statement: "For otherwise unaware editors, postmarketing is also known as Phase IV clinical trials" - is central to the problem.io_editor (talk) 01:06, 15 April 2008 (UTC)

Crohnie, thank you for all of this hard work. I think it reconfirms that the adverse effects merit a place in this article, which itself is a position backed by MEDMOS and common sense. Antelan^talk 15:42, 13 April 2008 (UTC)

I agree, worth a mention - however, not a media circus as is now posted.io_editor (talk) 02:06, 14 April 2008 (UTC)

By 'media circus', which references are you referring to? Liver damage is currently sourced to citations 23-29. 23 is to the letter sent out by Biogen/Elan to health care practitioners, with a 'lay summary' from a news source specializing in medical reports. 24 is the FDA. 25 is the European Medical Agency. 26 is to a page written by a neurologist on a website reporting medical information, where all pages are reviewed by physicians (on the specific sub-page reporting on multiple sclerosis information). 27 is the NeLM link, which summarizes a press release by the EMEA, which could be replaced if you really want by three links to EMEA publications. 28 is by the American Pharmacists' Assocation. 29 is from Medcape, which is part of WebMD. So where is the 'media circus'? All news reports are from agencies reporting medical news only, and could be replaced by primary sources (but then we miss out on the summary). I don't see a 'media circus', but I do see a whole bunch of links by medical news service providers that all link to FDA or EMEA information. If you are concerned about the proportion of text dedicated to this, you could find more sources that discuss natalizumab directly and expand the rest of the page. Then the proportion of text dedicated to the liver and PML issues would be reduced and the rest of the page expanded. 10 sentences, almost every single one of them with an appended reference, in two paragraphs, on a 25K page, doesn't look like a 'media circus' to me. As for being a 'severe' problem, I've replaced 'serious' with 'clinically significant', as that is the language used by Biogen and Elan. The rest of the wording comes directly from the sources I believe, and two agencies and the manufacturer think this is a significant problem. So, no 'media circus', no exaggeration of the potential or seriousness of liver damage. No problem with the page. Such is my analysis. The page is based on sources. The volume of text occupied by the section represents the sources quite well. Get more sources and expand the page if you'd like. WLU (talk) 14:05, 14 April 2008 (UTC)

You describe "a whole bunch of links by medical news service providers" - which is journalism, inappropriate for a science-based Wiki - "that all link to FDA or EMEA information" - the same minor issue, but repeated ==> wp:weight.io_editor (talk) 01:06, 15 April 2008 (UTC)

Well why don't you edit to reflect this then, instead of carping about it? Replace the news sources with primary sources from the FDA, EMEA and Biogen/Elan's own publications. That would improve the page. WLU (talk) 01:17, 15 April 2008 (UTC)

Here you go! Now all the 'popular' sources have been replaced with direct citations of the EMEA and Biogen/Elan publications. Thanks for the prompt by the way, I had missed the NEJM letter about melanomas. Your statements were instrumental in bringing it to my attention for inclusion. Huzzah!

The only remotely popular source, that is the only source that is not published by the FDA, EMEA, manufacturer or a recognized peer-reviewed journal is the publication by Gross. I say it's not a problem because it's clearly attributed to an individual, it's clearly his opinion and analysis and it's sourced to an award winning website that features content that is always reviewed by a medical practitioner. So, anything else? WLU (talk) 01:53, 15 April 2008 (UTC)

First my apologies for posting above then disappearing again. With a chronic disabling disease I cannot tell when my system is shutting down thus my disappearing like I do. Now as for WP:Weight being claimed for listing the adverse effects to the article, I'm sorry but I see no weight issues at all. Patients coming to the page need and want to know about all side effects, even the ones that are always used as a CYA for the company. Knowing about possible liver damage, brain damage and death possibilities with use of this medication or any other medication is necessary to inform, not a 'scare tactic' but necessary. This is fairly a new medication, and I am not medical like a lot, well most of you here so I don't post fancy, but I do try to say things honestly of how I feel about things. The side effects are listed in many WP:RS as shown. I don't know if any of you are patients or in the medical field, though I suspect some of you are from the way you post and I know one is learning. Weight has to be considered, yes this is true, but weight also has to give value to the information provided in the article so that people reading the article can go there and learn with enough information to talk to their doctors intelligently. Now that said, too much information is also not good for a patient especially because it can frighten them so much that they do not listen to advice from anyone, even their own physicians. But, tell of serious side effects to vital organs or possible death is not scaring people away from using a medication. Just like this medication, most medications used for MS and IBD in general have the same kinds of side effects requiring the patient to be monitored at all times to make sure that damage is not occurring. I just reread the article, thank you to whoever put in the possible liver damage information, and I think the article reads with balance though I have to say that some of it reads to technical for someone like me, a layperson, to understand. I really think from my readings to date, trying to catch up on the conversations going on here that the issue of weight has been taken care of and is no longer an issue.

I understand that some may try to understand how a patient may think about things like this, and I hope what I say helps put some light on this matter. Patients want to know as much and even more than they should about their medications and other treatments. Patients tend to scare themselves by researching too much and not knowing where to research to get a fair analysis of information. This is what this article needs to do, direct the people to sites that give them information that is reliable so that they don't go to websites and listen to testimonial information from people they do not know. I think this article is headed in the right direction, of course this is just my opinion. I am concerned with the chart also, to me it sounds like the medication is a possible magic bullet with the numbers shown. There is no magic bullet for chronic incurable diseases and putting a chart up that may insinuate that there is to me is showing an illusion or even suggesting a possible cure is currently knocking on the door. This is not the case unfortunately for MS or CD, I wish it were but right now it's not. I hope I am making sense, trying to catch up on conversations as long as this one is really difficult to do. Thanks for listening to me, --CrohnieGal^Talk 15:37, 17 April 2008 (UTC)

Crohnie, the WP:Weight is not for simply listing adverse effects. My objection is that the subsequent liver reports gets huge space in the article, even though it was "invisible" in the many N clinical trials (the links I gave you above). Space should be given to how the drug helps. The only 2 other Crohn's biologics (Remicade, Humira) are both TNF-alpha inhibitors which should be both worse than N in this respect. I assure you, the liver issue as presented here - a dozen lines - is very heavy-WP:Weight.io_editor (talk) 13:32, 18 April 2008 (UTC)

Hi Io, if you had to take these meds, think about this, would you or would you not want to know about this possible side effect and any other serious effects? I don't think a blurb of a sentence or two about serious possible side effects does the reader any good to make a judgement about any medical decisions they have to make. You say it scares the patients from trying it, well this is true sometimes and also not true. My experience is that the people trying to make the decisions hunts out others like them and asks their experiences with what ever med being talked about. I'm sorry but I have to disagree with you and say that WP:Weight is not an issue here. I also think the Remicade page needs to have a side effect section added, not a section titled 'Safety' which is deceiving in it's title to me. Sorry, just my opinion, --CrohnieGal^Talk 14:14, 18 April 2008 (UTC)

That's your own analysis and there is no undue weight since the PML and liver concerns are mainstream. Also, wikipedia is not a how-to manual and should not be written as such. Space can be given to how the drug helps, all you need to do is source, and write or expand a section on this. The page is not finished and no-one has said it is. If you've got more reliable sources on how natalizumab works, its effectiveness or any other relevant information, you are not forbidden to add it. So do so. I am at a loss for complaints since there's plenty of room and reason to expand the page, thus appropriately reducing the proportion of text dedicated to side effects. WLU (talk) 14:51, 18 April 2008 (UTC)

[edit] break

From my point of view as important as liver damage is I feel that all the second paragraph is not needed, not becouse it is not important, but because most of it is superflous or already said.: (Liver damage occurs in about 1 in 1,000 (0.1%), which may be similar to other immune-suppressing drugs used to treat MS.[26] At least 29 cases are known.[27] The liver damage appears to be reversible.[citation needed] Challenge-dechallenge-rechallenge indicates that the liver damage is due to natalizumab rather than being a coincidental occurence.[23] Liver damage may appear at any point, including among patients who have taken multiple doses previously without demonstrating illness or hepatotoxicity.[23] The symptoms produced by natalizumab are recognized as predictors of serious liver damage, possibly resulting in liver damage, need for a liver transplant or death.[23] If not diagnosed promptly, affected patients may die or require a liver transplant.[28] As of March 2008, no natalizumab patient had needed a liver transplant.[26]) It could simply be eliminated

Challenge-dechallenge-rechallenge: there is no need to explain how its liver damage potential is investigated.
The liver damage appears to be reversible: citation needed
Liver damage may appear at any point: well, this can be saved.
including among patients who have taken multiple doses previously without demonstrating illness or hepatotoxicity: its saying the same again (if it can appear at any time, this is obvious)
The symptoms produced by natalizumab are recognized as predictors of serious liver damage: alredy said in previous paragraph
need for a liver transplant or death.[23] If not diagnosed promptly, affected patients may die or require a liver transplant.: as any serious liver damage, so why say it. enough to add an internal link to hepatotoxicity.
As of March 2008, no natalizumab patient had needed a liver transplant.: thank god... but it does not really mean anything. Liver damage is no less important with this sentence, and it implies that liver damage is not so important while even if nobody has needed a tranplant liver damage is very important.

--Garrondo (talk) 14:41, 18 April 2008 (UTC)

I numbered so I can comment on a per-sentence basis. 1 I'd say is important because it demonstrates that natalizumab is the causative agent. 2 I see your point. 3 and 4 I think should be kept - the general idea is that previous history of safe use without side effects is no guarantee of future safety. 5 I agree, cite 23 should be repeated after 'severe liver injury' in previous paragraph. 6, the potential for death or transplant should be somewhere but would not be hard to do. 7 I agree. I'll have a go, see what it looks like in, say, 20 minutes. WLU (talk) 16:42, 18 April 2008 (UTC)

I dont have 20 minutes, but this liver issue is not only extremely rare with N (with > 4,000 patients => 2 years dosing, it did not exceed placebo occurrence by 1% in ANY of 5 trials - nor was it seen in the earlier phase 1 nor phase 2 safety trials); it is also a drop-in-the-bucket - it would take gross negligence for a patient to get into trouble - and they already have BIG trouble with MS or CD. Its an almost irrelevant risk compared to what N does (even simply preventing an MS patient from falling down; or getting a CD patient into remission; etc). Its nothing more than a routine Dear Doctor letter - in serious progressive diseases the interets of the drug companies and patients are a lot more aligned than, say with aspirin.io_editor (talk) 17:08, 18 April 2008 (UTC)

Also I forgot to say that the Liver is pharmacutically by far the most sentive organ in the body - there are millions on statins and they have to look out for it too. The whole focus on liver injury is bogus.io_editor (talk) 17:08, 18 April 2008 (UTC)

'Taint purty but it's done. If the FDA, EMEA and Biogen/Elan think it's important enough to change the label, then who are we to argue? Source > opinion. WLU (talk) 17:15, 18 April 2008 (UTC)

Garrondo,

Here's my perspective: #1 was included because of the fussing of one editor about the potential for liver damage not being sufficiently "proven" because it wasn't determined in a randomized controlled trial. Fine: we never claimed that it was. CDR also matters because it suggests that going back to the drug in the same patient has a higher likelihood fo recreating the same problem for that individual (whereas something like an infection due to immunosuppression probably wouldn't). #2 is the still-unsupported belief of said editor. Consider it another failed invitation to provide the source to support this belief. #3 and #4 are purposefully redundant to improve readability: general concept in small words, repeated in big words. From the perspective of patient advocacy, this is also valuable because it explains why you have to keep getting a liver panel. #6 explains why liver damage matters, in practical terms, to non-experts. I already know that, you already know that, but it's unreasonable to assume that all, or even most, average readers already know that. #7 was included to provide proper context for this adverse effect. I'm not trying to make the drug sound any worse (or any better) than it actually is, after all.

Basically, I'd restore most of the deleted information, but the outcome is not critically important to me. I appreciate your comments. WhatamIdoing (talk) 18:55, 18 April 2008 (UTC)

Terrible, terrible snob that I am, I say if the readers don't understand the page they click on the links or get a dictionary! I'm the worst, most eliteist editor EVAR! I see all the information in the earlier version as preserved in the current version, and duplication has indeed been reduced, which pleases me. The guts are there, and I prefer the more compact current version. WLU (talk) 19:07, 18 April 2008 (UTC)

[edit] Undue weight

Let's bury the undue weight issue once and for all. It comes up a lot, and it's kinda ridiculous. Wikipedia:Neutral_point_of_view#Undue_weight, if you actually read the section, is about minority views and how much text to give the minority position within a main article that is supposed to place the most emphasis on the majority position. So on a page about medical treatment of condition X, most of the text goes to drugs, surgery and other pubmed sources discussing mainstream treatment options, with a small amount of text discussion acupuncture, prayer, ear candling and other minority and alternative treatments. On a page about evolution, most of the text discusses the change in morphology, genes and fossils, with only a tiny bit of text discussing creationism and the US-based political and educational clash. On a page about Hitler, the majority discusses his political, military and personal biography, with only a short section on his vegetarianism and sexual proclivities. So, undue weight is found if large portions of the article deals with views which are not held by the mainstream. Since the mainstream is pretty much defined by that reported in reliable sources, a page gives undue weight if the text deals more with concerns expressed in unreliable sources than it does in reliable ones. Given the gross preponderance of sources that are from medical journals, regulating agency and manufacturer publications, I'm of the very strong opinion that the page gives due weight to the opinions of mainstream sources. Pending reliable sources that either through explicit discussion or pure volume of discussion, demonstrate that the risks of PML and liver damage are minor or of no consequence and represent a minority position on the impact of natalizumab on MS and the market in general, I think any further citation of WP:UNDUE as a reason to change the page is bollocks. Henceforth, I boldly suggest that such statements by Io Io editor, the sole individual who seems to think that there is any merit to the discussion of undue weight placed on natalizumab's side effects, should immediately be userfied to his talk page as tendentious and disruptive editing.

To summarize, the criteria for undue weight is undue emphasis on unreliable sources or viewpoints held only by the minority. Io, if you wish to adjust the page per WP:UNDUE, you must present reliable sources that explicitly support your point and not argue using original research. WLU (talk) 14:23, 15 April 2008 (UTC)

[edit] MEDMOS and Wiki de-facto standard for treating the Liver issues

When I suggested a "Corrollary" of "liver injury leading to N" - what I meant was that, because liver injury is generally much higher in the other DMDs for MS and Crohns, it is certain that a fair percentage of patients in both disease classes, failing the respective DMDs due to liver issues that wont go away, will find - and today are finding - in N a haven. Now, indeed MEDMOS / drugs, guiding how Drug pages be written, writes "For example, a long list of side effects is largely useless without some idea of which are common or serious. It can be illuminating to compare the drug with others in its class...." Accordingly:

[edit] Multiple Sclerosis DMD class

Interferon beta-1a - Avonex & Rebif - deespite grave [Primetherapeutics outcomes and also per page 8 of label - in just 48 weeks liver injury occurred in 18% of Rebif and 10% of Avonex patients.

Betaseron - liver issues up to 12% of treated (3x or 4x placebo) per label.

Glatiramer acetate - not in pivotal trial (< 10% of N trials' size), but see page 16 for "liver function abnormality; liver

damage; hepatitis; eructation; cirrhosis of the liver".

Mitoxantrone - I didnt look at it, usage will always be rare.

[edit] Crohns Disease DMD class

Infliximab - On page 29 of label "Some of these cases were fatal or necessitated liver transplantation" - on Pages 39/40, elevated scores in 30%-40% range of treated patients.

Adalimumab - On page 36 of label - "In some cases patients have died as a result of hepatitis B virus being reactivated".

- What all the Wiki pages for these drugs have in common is that the liver issue is consistently relegated to just a single line, usually "rare reports of serious liver injury". This submitted here for new light on the dozen+ lines on “liver injury” on the N page - none of which have had ANY serious patient outcomes reported. io_editor (talk) 14:13, 18 April 2008 (UTC)

Well, at least it's not WP:UNDUE. Comparing natalizumab to other drugs without a source that explicitly does so for us is a WP:SYNTH. Stating that natalizumab is 'a haven' for individuals with MS and CD, without a source, is a grossly egregious violation of SYNTH and WP:NPOV because it asserts, without evidence, that the drug is superior to its competitors. And the article provides not a 'long list of side effects', but a short list, and the two longer sections for PML and liver damage both provide an incidence number (.1%). Based on a search of "natal" and "tysa" on all of the pages provided, I found no mention of natalizumab or tysabri. I think the representation of liver damage is fair and accurately represents the sources that are cited to support the statements. Therefore, there's no need to change the page because of two policies. The MEDMOS guideline does not trump adding our own analysis in contravention of policy. WLU (talk) 14:45, 18 April 2008 (UTC)

Just because [{User:WhatAmIDoing]] and you invent the statement that "Liver damage occurs in about 1 in 1,000 (0.1%), which may be similar to other immune-suppressing drugs used to treat MS" - which you can see, in black-and-white on the other MS drug labels, to be a "a grossly egregious violation" of scientific logic - doesnt mean that the World of Clinical Medicine is going to run out to do a comparator clinical trial to see if your commonly-held wp:OR might be anywhere close to reality.io_editor (talk) 16:38, 18 April 2008 (UTC)

Source > analysis by editor. Source also > scientific logic. Always. Don't care about other drugs. WLU (talk) 17:39, 18 April 2008 (UTC)

[edit] The 900 other drugs that cause Liver Injury

The manner in which the hundreds of other Wiki editors have written hundreds of other pharmaceutical pages is the de-facto Wiki standard.
The Hepatotoxicity page reveals that 900 other drugs cause Liver Injury.
Drugs causing liver injury include Tylenol where you can read that it alone causes 50% of acute liver-related hospital admissions in USA.
Other classes include VERY COMMON drugs:

--1. NSAIDs, consisting of aspirin, advil, phenylbutazone, sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin.

--2. Glucocorticoids consisting of Hydrocortisone, Prednisone, Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclometasone, Fludrocortisone, Aldosterone]].

A quick look at all of these pages and most confine mention of the liver issue to a single sentence. Only real comparable to N page is Tylenol.
Also listed on the Hepatotoxicity page are:

--3. Natural products (mushrooms!) and

--4. Herbal and alternative remedies

Looking at herbalism reveals no mention.
Clearly the treatment of the liver issue on the N page is unique among all other Wiki pages of drugs known to cause liver injury, and is therefore very heavy-wp:weight.
- This is not evidence of undue weight. Presenting a minority viewpoint with equal prominence as that given to a majority viewpoint is undue weight. Treating an aspect of a subject as overly significant to the subject is undue weight. Fvasconcellos (t·c) 17:27, 19 April 2008 (UTC)
The great majority of these drugs, being over-the-counter medicine, are easy to over-dose on. With N, that is impossible.
Remembering too that NONE of these are Disease-Modyfing Drugs proven to arrest Serious Progressive Illness. If you get a liver injury from something in your medicine cabinet, then it is the worst thing you have. However if you get the liver injuries that have occurred in the 0.1% of 20,000 N-treated MS and CD patients, then the worst thing you have is still MS and CD.io_editor (talk) 14:54, 19 April 2008 (UTC)

This does not matter. If an adverse effect features prominently in reliable external sources, it is worth mentioning here. Liver injury is indeed a possibility with hundreds, if not thousands, of drugs. Natalizumab certainly hasn't been the only drug associated with PML, and there may be far stronger causative links between PML and other drugs. Nonetheless, it is worth mentioning. Think of natalizumab as a topic, an universe, a set. The weight given to each aspect in the article—mechanism of action, adverse effects, history, availability, efficacy, even things not yet covered such as cost—should be judged against the relevance of the aspect within the natalizumab "universe" and against the prominence they are given in reliable external sources. Fvasconcellos (t·c) 17:27, 19 April 2008 (UTC)

These guys know well (example) that NOWHERE have I said that the Liver issue should be deleted entirely - that is NOT the issue. Instead the page has concocted a big rigmarole around, with a number of FALSE facts and repetitive citations. Its just a precaution that is being exploited, and obviously inconsistent with Wiki precedent.io_editor (talk) 17:35, 19 April 2008 (UTC)

They have known for 10 days that I did NOT object to Liver mention - but they choose to spin it that way.io_editor (talk) 18:10, 19 April 2008 (UTC)

I agree that there is unnecessary repetition of content in the page, and I was just about to propose some reorganization below. If you don't think mention of liver injury should be removed, what is the issue regarding it? Fvasconcellos (t·c) 17:42, 19 April 2008 (UTC)

OK, I will cut-and-paste the main points, I believe there are 3 or 4 -

1.The very first words of the paragraph describe that the evidence comes from "{[post-marketing trials]]" as added by User:WLU here based no doubt upon informed advice from User:Antelan here. That is complete hog-wash, designed to show a proven cause by N ? Instead the "Dear Doctor" letter says is that "clinically significant liver injury has been reported in patients treated with TYSABRI in the postmarketing setting". It refers only to reports by individual doctors on a handful of individual patients (out of 20,000+) in ordinary use, not clinically supervised or vetted... Neither the drug companies nor the FDA are in a position to review such cases from base-line (no record of course), nor their causes. Once a report is duplicated a number of times, all the drug companies can do is write the letter, and the FDA publishes. Its just a precaution against the possibility that something serious might happen.io_editor (talk) 18:10, 19 April 2008 (UTC)

I've edited that to point to Postmarketing surveillance, which I felt to be more accurate. Fvasconcellos (t·c) 20:27, 19 April 2008 (UTC)

2. The page was originally editted 2 weeks ago by User:WhatAmIdoing to say that "which may be similar to other immune-suppressing drugs used to treat MS" based upon one of the many generic (not specific to MS or CD) web-based health sites here. Not only is this a crap source, it does NOT make any such comparison, and should be deleted as below encylcopedia standard.

I don't see that statement in the article. I do agree we should find a more solid source, though. Fvasconcellos (t·c) 20:27, 19 April 2008 (UTC)

There will be no such solid source, its just wp:OR.io_editor (talk) 20:33, 19 April 2008 (UTC)

3. The page now compares liver injury N to ALL "immune-suppressive drugs" as a class. This is very dubious wp:OR, but is also demonstrably false. The majority of immune-suppressive drugs are steroids, whose very mechanism-of-action depends upon the liver enzymes; and you can read the interferon numbers here and TNF-alpha-inhibitors numbershere, up to an order of magnitude larger than for N.io_editor (talk) 18:28, 19 April 2008 (UTC)

The sentence simply doesn't specify which immunosuppressants are also associated with liver injury. Changing it to specify which ones would be more than reasonable. I don't think comparing incidence is necessary, but if you've got sources, go ahead and alter the statement. Fvasconcellos (t·c) 20:27, 19 April 2008 (UTC)

I already gave the sources, the FDA labels for interfrons and TNF-alpha inhibitors, plus the hepatoxicity page listing the sterois as a group. What other sources do I need before I can remove unsourced wp:OR?io_editor (talk) 20:33, 19 April 2008 (UTC)

Relax, I wasn't asking you to provide more sources. Fvasconcellos (t·c) 20:36, 19 April 2008 (UTC)

4. The page makes huge mileage out of non-trial reports of liver-issue single-patients who came to no real harm, and of course remain with serious MS problems. To put such detail here, including the challenge-rechallenge, and 6-days stuff is inappropriate because it did NOT happen in the investigational setting.

5.Furthermore I would point out that, in addition to these single-patient reports (not papers, just secind-hand reports), there are already the 3 papers on single patients having PML on the page. Everything that I said before on the PML issue stands, because of *those events occurred in a combination therapy no longer in use; *all the PML cases went undiagnosed for a minimum of 3 months each; *A number of medical institutions have written to publicly question if there patients really had MS, due to lack of MRI and post-mortem evidence; *Finally, hundreds of others editors have set the Wiki standard for editting pharma pages for DMDs trating serious progressive diseases, and yet neither here nor here do I see comparable expansion of a safety issue - specifically to be in the article lead, and in 4 separate sections, far outweighing the extent N has proven to help.io_editor (talk) 18:45, 19 April 2008 (UTC)

[edit] FDA new safety plans on drugs and biologicals

I really don't know if this has been discussed so I thought I would go ahead and bring it to everyone's attentions just in case it hasn't been (too lazy to read through everything to check!) http://www.fda.gov/OHRMS/DOCKETS/98fr/E8-6201.htm I forgot to say, if someone here with the medical knowledge could explain what this actually means I would appreciate it since a couple of my meds are on the list. --CrohnieGal^Talk 16:42, 19 April 2008 (UTC)

It might merit a single sentence in the ==Legal status== section. I've explained the rest on your talk page. WhatamIdoing (talk) 04:25, 20 April 2008 (UTC)

The article states that N has already an approved safety plan under this policy.io_editor (talk) 18:00, 20 April 2008 (UTC)

[edit] Legal status

I am not happy with the current state of the "Legal status" section. It's a bit of a timeline-style mix of historical, pharmacological, and legal aspects, and I think it could be better focused. I know there will probably be some opposition, but what do other folks think of collating most of the PML info under a subsection of Adverse effects? I think the fact that this information is currently strewn across several sections may be adding to perception that PML is overrepresented in the article. Fvasconcellos (t·c) 17:53, 19 April 2008 (UTC)

Hm. The release, removal and release is a big aspect of the drug, and should be represented. That PML was the cause is far less important than the actual out-in-out, but to not mention PML leaves the huge question of why it was withdrawn and anyone who was reading the page would be curious about a lack of mention. I don't really see the specifics of PML as being vital to the section though, so I say edit, then let's see what's left. WLU (talk) 18:55, 19 April 2008 (UTC)

Sure. I don't think cutting PML from "Legal status" would negatively impact the section. Since PML is mentioned in the lead and there would be a subsection on it, the only way a reader could not pick up on the fact that it was responsible for withdrawal would be if we (a) removed all mention of PML in the section, which would be unnecessary, and (b) they went directly to the "Legal status" section. Against my better judgment, I'll be bold and move some stuff around. Feel free to tell me what you think. Fvasconcellos (t·c) 20:03, 19 April 2008 (UTC)

By the way, can anyone confirm if the surviving patient referred to in PubMed is the subject of PubMed? Fvasconcellos (t·c) 20:12, 19 April 2008 (UTC)

Yes, but I see you have elevated PML to it's own section. Please explain.io_editor (talk) 20:19, 19 April 2008 (UTC)

We've discussed this—PML was notable enough, however few cases or tenuous the causative link, to feature prominently in the article. Putting it in its own section also prevents information from being spread out all over the place (I remember you objected more than once to PML being mentioned in three or four sections) and keeps the other sections focused on what they should focus on (i.e. Legal status focusing on regulatory aspects instead of providing a unified explanation of the PML scare and natalizumab's withdrawal/return to market). Fvasconcellos (t·c) 20:31, 19 April 2008 (UTC)

Its still in 4 sections, including the lead, and as you know, there is no comparable in all of WikiMed for a DMD treating a serious progressive disease for such treatment. Nevertheless, please excuse me, you are still working on the page, I thought you had left it.io_editor (talk) 20:37, 19 April 2008 (UTC)

(undent)The number of places PML is mentioned is irrelevant. The relevant issue is if the mentions are justified in each section, if removing PML makes the section less informative, not gross number. The lead must mention PML because it is such an important aspect of it's history. The question to ask is 'is the page better with these changes?' Not 'does this make PML more prominent or not'. That kind of question is wholly inappropriate as it points to a significant bias and WP:NPOV issue. WLU (talk) 01:06, 20 April 2008 (UTC)

Noobody is responding, so I will give my opinion:

You write that the "number of places PML is mentioned is irrelevant". That is the main content dispute issue. Here, it easily out-numbers the combined total of mention on the Wikis of all other drug causative agents.
You ask a simple question: "is the page better with these changes?" Fair enough, and my answer would be No, because these mentions vastly outnumber mentions of what the drug has proven to do. In fact PML is currently the single consistent message of the page, top-to-bottom. I suggest that you and others take a good look.io_editor (talk) 18:00, 20 April 2008 (UTC)

The information moves make sense to me Fvasc and the paragraphs read fine. I would say that the veterinary use section should probably be put back as an invisible section title - it doesn't really matter since it's invisible and empty, but it's a placeholder for a possible future section. WLU (talk) 01:32, 20 April 2008 (UTC)

[edit] PML and interactions

Re-reading the adverse events section and PML, I've a thought. PML only occurred when combined with interferon, does it make sense to put the PML information into adverse effects? What about moving the whole section on PML in AE into interactions? A source says that the 3 events occurred only when combined with interferon, that suggests interaction, not an effect of Natalizumab alone. Thoughts? It would also reduce the mention of PML on the page, but in an appropriate way and contain the same volume and detail of text. My concern is that it buries the very important PML issue too far down the page, and I don't think there's consensus (yet?) for a reorder.

Another option is PML having its own separate heading, and putting all PML-related information in that section. Legal status would retain approval perhaps. PML is important enough to the history of the drug that it should be prominent, but it bridges a variety of otherwise separate sections. Did someone else already suggest this? WLU (talk) 14:35, 20 April 2008 (UTC)

Nobody responded, so I will. You dont give many details of your suggestion. I would be interested in hearing more of what you say; perhaps the AE or the Status section (move it up) is better than the interactions. I will write something of my own off-line mid-day tomorrow.io_editor (talk) 03:27, 21 April 2008 (UTC)

Tah dah! I've been bold, who wants to revert and discuss? WLU (talk) 18:22, 21 April 2008 (UTC)

[edit] Proposal for N new content/format

Seeing no further details of WLU's suggestion, and as the page got some Admin interest now, I am going to propose the following:

Lead/notable – keep the “PML/deaths etc”, insert this as N is reliably seen as a notable medical advance over older drugs;
Inter-Actions – delete entirely. This may be MEDMOS, but its only a guide not a requirement, and the reason it is there is for medicine cabinet pills. It is inconceivable for N to interact with Avonex.
Indications – First put the benefits into a bulleted list, as the prose is poor as it is already more a list than an essay. Then, add a “Pediatric treatment w/N” sub-section, based upon several focused individual case or small group studies, some suggesting reversal of disease course, - here, here and this (as the web-site is a national-level MS society). After all, there are 4 or 5 adverse individual case histories already cited on page. Finally, delete the antibodies part reducing efficacy, which is mis-leading as the same antibodies reduced efficacy in the trials themselves down to what was reported, and furthermore it is common to all biologics.
Adverse Events:
1. Liver issues – just like any other WikiMed page. One line. Cite the Dear Doctor letter only.
2. PML – keep, but its too long, repetitive, case histories, etc, leave out the silly stuff about “patients who have already had PML” (one every century?), no need to repeat patient registry here, and leave out “scientists hypothesize…” etc – there is a PML page and a separate journal called Medical Hypotheses for that.
Legal Status (by the way, I think MEDMOS wants to say “Regulatory Status” or just “Status” or “Current Practice” – to me “legal” means “lawful” in the USA) –the PML is not bad, and registry bit up to date with this.

So, just say Yes or No. I don’t really like it, as the only common thread page on the page is PML, being still in 3 separate sections plus the Lead (which I think in 6 months time will odder and odder, because patients cannot get N+Avonex, and they sure are not getting PML) …..io_editor (talk) 17:02, 21 April 2008 (UTC)

Need the full text to see why it's a notable advance, otherwise a potentially good source. Though is it an article, or a letter to the editor? Both can be used but must be treated differently.
No. Sourced, though I still think the PML info could go here.
Nervous about single-subject research, but the second reference should be added. No need for a sub-section as it's only one added article - a sentence or two should be adequate. The third is a personal story, no. Leave in antibody text as the whole source is about antibodies; without a source indicating that this information is erroneous or irrelevant, leave it in.
Leave in liver damage and I still think PML could be better placed in interactions.
Possibly retitle legal status as 'release history' or put in history - there's no real court cases, it's about how the drug is regulated in the US and Europe. News article could replace reference 30 (no new PML since X date).

PML will never be removed from the lead. Stop counting it as a mention. The lead should summarize the body text, please review WP:LEAD for more information. If the body text puts significant space into an issue, it must be in the lead as well. Liver damage is not, but PML is and should be due to how the drug was and is regulated (and this is exactly how the lead treats PML). In my mind, PML should be in interactions and legal status. I think I'll boldly move it out of adverse effects and into interactions. WLU (talk) 17:35, 21 April 2008 (UTC)

Hyams et al has been added to the CD indications section - basically saying it seems to work for adolescents too. Also used it and another reference to expand side effects a little. WLU (talk) 18:46, 21 April 2008 (UTC)

It is neither an article, or a letter to the editor, it is the editorial of the N issue.
Even Admin:FV said the Liver could be editted - his specialty seems to be drugs.
You are "Nervous about single-subject research" but there is already many single-subject research papers on the page.
As for the rest - I tried - and now I see that efficacy has caught your eye.io_editor (talk) 02:24, 22 April 2008 (UTC)

[edit] Efficacy

To be brief, you have closed the Indications/MS sub-section with this:

"Natalizumab offers a limited improvement in efficacy compared to other treatments for MS, but due to the lack of information about long-term use, as well as potentially fatal adverse events, reservations have been expressed over the use of the drug outside of comparative research with existing medications, with ref name="pmid18354844".

But the full paper is free, and its conclusion is totally different:

"Uniquely, among the trials of DMTs, significant efficacy was seen in nearly all primary, secondary, and tertiary endpoints, including the quality of life measurements. Although direct head-to-head comparisons have not been performed, the preponderance of data strongly supports the notion that natalizumab offers greater efficacy than existing DMTs. Clearly, since MS is a life-long illness, it is important to recognize that the benefits found on relatively short-term measures seen in clinical trials may not translate into long-term effects in the prevention of disability progression. Natalizumab is not a cure for RRMS but it is a significant improvement on current therapy and given its efficacy and tolerability, natalizumab fulfills an unmet medical need in the treatment of MS."io_editor (talk) 02:24, 22 April 2008 (UTC)

Nope, I mixed up the ref name template between Hutchinson (pmid = 18360634) and another article (pmid = 18354844). In this edit, I tried to fix and as I say in my edit summary, I think I got them all. Lesson for the children - never rely on just the first three pubmed numbers. From the abstract, "In practice, given the poorly assessed and potentially fatal risks of long-term treatment with natalizumab, the limited improvement in efficacy does not justify the use of natalizumab other than in comparative trials." I used "reservations" because Hutchinson and pmid 18354844 seem at odds. There's a lot of information out there, I'm limited by what I can find mostly on pubmed. WLU (talk) 12:28, 22 April 2008 (UTC)

[edit] Image

The page has a single image of a generic antibody. What do people think about adding this image? It'll add a bit more to the page and I believe N is infused via injection. Could it be placed in the infobox or is that reserved for chemical structure alone? I couldn't figure it out from the template page. WLU (talk) 18:38, 28 April 2008 (UTC)

It's not perfect. This looks like a set up for a bolus injection (all the drug shoved in at once), and natalizumab is infused over the course of an hour, using either a pump or a syringe driver. WhatamIdoing (talk) 01:32, 29 April 2008 (UTC)

You could consider You might consider a bunch of IV bags or this IV in hand as alternatives. I think they're both public domain. Something like this (not free) might be nice. Surely WP has such a photo somewhere? WhatamIdoing (talk) 01:57, 29 April 2008 (UTC)

If we can find out if this one is copy protected I think it's the most appropriate "here" I am talking to my mentor and friend, Delldot about how and if this can be used. --CrohnieGal^Talk 12:13, 29 April 2008 (UTC)

Oddly enough, I managed to get a reply to an e-mail I sent to a generic account at Elan. They said they couldn't give us an image, but I might be able to get a fair use rationale out of the image yet. WLU (talk) 19:41, 29 April 2008 (UTC)

Talk:Natalizumab

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Contents

[edit] Archive

[edit] Stem cells

[edit] FDA did not withdraw Tysabri nor cancel it's License

[edit] the PML deaths

[edit] How many "real" MS patients on N (and Avonex) got PML?

[edit] Today's MS Society (UK) 12-page pull-out on MS in London Times

[edit] End of archive

[edit] Analysis article on the other PML death

[edit] MEDMOS: "compare ... with others in its class" (auto-immune)

[edit] Europe?

[edit] N allegedly leading to "liver injury" (and corrollary)

[edit] Remove NPOV tag?

[edit] Review article

[edit] The corrollary: - in fact "liver injury" leading to N (?)

[edit] break

[edit] Undue weight

[edit] MEDMOS and Wiki de-facto standard for treating the Liver issues

[edit] Multiple Sclerosis DMD class

[edit] Crohns Disease DMD class

[edit] The 900 other drugs that cause Liver Injury

[edit] FDA new safety plans on drugs and biologicals

[edit] Legal status

[edit] PML and interactions

[edit] Proposal for N new content/format

[edit] Efficacy

[edit] Image

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