Talk:Treatment of multiple sclerosis

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Featured article star Treatment of multiple sclerosis is a featured article; it (or a previous version of it) has been identified as one of the best articles produced by the Wikipedia community. Even so, if you can update or improve it, please do.
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Contents

[edit] Scientific peer-review

Wikipedia:Scientific peer review/recent reviews I have asked for scientific peer-review of this article. I would appreciate any ideas to improve or to correct any mistakes there may be. --Garrondo 08:40, 1 September 2007 (UTC)

[edit] A good idea

It's a good idea to off-load this article. Thanks for doing it! InvictaHOG 19:16, 28 October 2006 (UTC)

[edit] Clean up

I`m trying to clean up the article. It does not have proper references and the format varies from one section to other. It was specially bad written the investigation section where severel non NPOV could be found. I have divided it in two sections: investigations in II and III phase clinical trials and basic investigation.

Cleaning up I have eliminated the following paragraph:

  • The use of cytokine and immunological agents to modify the auto-immune component to MS have proven to be beneficial but not without side-effects. Tumor necrosis factor blocking agents are coming out to halt the immune response to chemotactic signalling associated with localized inflammation. The Millennium Health Centers has found that returning IGF-1 levels back to a median to high normal physiological level, will help modify the status of MS. Initial patients have gone into remission and then stopped use of growth hormone for up to 12 months berfore symptoms started to reappear. Article have been published in mainstream publications citing the CYTOKINE MODULATION of Growth Hormone.

The reason to eliminate it is that I can´t really understand what it talks about; and neither can I find the articles it talks about in pubmed. If anybody understands it and can help to improve it be welcome... If not it will be lost

[edit] Finished my clean up

After a whole month working in the article I think I have finished improving it. I have added more than 60 references, reordered much of it and moved some information very similar to lists to secondary articles. I think is a much better article than a month before. Therefore I'm thinking of nominating it for "good article"; however it may be difficult to get it becouse it doesn't have any pictures. The problem is that I can't think of any pictures that fit. Any ideas? Does anybody think it has some possibilities? --Garrondo 14:22, 31 August 2007 (UTC)

May I suggest the structure of mitoxantrone? There is no published crystal structure of natalizumab, although that would look cool :) Image:Methylprednisolone.svg might be appropriate for "Management of acute attacks". Structure images are usually a good idea when there is nothing more appropriate. Fvasconcellos (t·c) 15:21, 2 September 2007 (UTC)

[edit] Therapies for multiple sclerosis good article candidate

I have nominated the article as a good article candidate. I would be thankful to anybody who who helped in the good article review (See: Wikipedia:Good article candidates If you have not contributed significantly to this article, feel free to evaluate it according to the good article criteria and then pass or fail the article as outlined on the candidates page. --Garrondo 13:27, 5 September 2007 (UTC)

[edit] Alternative therapy

In consideration of the 500,000+ hits on Google when searching for tai chi and multiple sclerosis, I think it behooves those looking to create a comprehensive, GA-status article to do some investigating and potentially include a mention. It would seem that many published works also touch upon the practice as an MS therapy, as do more scholarly sources. VanTucky Talk 23:29, 12 September 2007 (UTC)

[edit] GA Review

This article is very well written, with relatively easy to understand prose, and sufficient reference citations. It has a good, well-written, lead section, and good use of images. As written, I beliee this article meets the Good Article criteria, and will be listed.

A couple of areas of improvement: first, the section headers seem to be kind of long and wordy. Perhaps they could be reduced or paraphrased a bit. Although they do seem to be an accurate description of their contents, so I'm not sure how to go about reducing them. Maybe something as simple as combining the 'management of...' headers into one main section, with subsections, would reduce the repetition of the 'management of...' line, making it a bit easier to read?

Second, under 'Management of relapsing-remitting MS', the second to last paragraph, dealing with ease of use, price and side effects, is unsourced. As some information on the frequency of injections is provided, a reference should be added (though, given the well-sourced nature of the article as a whole, I won't withhold GA status over this one issue). I think that the earlier references for the drugs, a few paragraphs up, probably have this information anyway, so they could be used here.

I like the look of the chemical structure of methylprednisolone, and compared to the structure of mitoxantrone, the lines used in the structure of the latter are much weaker and less apparent than the former. Perhaps the structure of mitoxantrone could be improved a bit in the

image file to use darker lines, and maybe increasing the size of the image just a bit, so more closely match the look of methylprednisolone.

Also, a suitable image for the upper right-hand corner, to be used as an intro, would help to better grab the attention of the reader. I don't think an infobox is needed here, but a good lead image would be nice.

Hope this helps improve the article even more! Good work so far! Dr. Cash 21:03, 18 September 2007 (UTC)

Sticking my nose in—I've created a new structure of mitoxantrone to match the methylprednisolone one. Fvasconcellos (t·c) 02:14, 19 September 2007 (UTC)

[edit] Featured article

I have nominated the article for featured article after working on it after it become a GA. If you think the article is good enough please vote for it. Any comments for improvement will also be welcomed.Garrondo 13:41, 25 October 2007 (UTC)

[edit] Rename to Treatment of multiple sclerosis

I would suggest moving this page to Treatment of multiple sclerosis, consistent with articles such as Treatment of Crohn's disease, Treatment of bipolar disorder and others. If nobody objects I will go ahead and rename the article. --WS (talk) 23:33, 16 November 2007 (UTC)

Done. --WS (talk) 19:49, 19 November 2007 (UTC)

[edit] benefits on physical variables

"Some studies also show benefits on physical variables" ... what the heck does that mean? Isn't there a more straightforward way of saying it? Leotohill (talk) 05:53, 24 January 2008 (UTC)

[edit] confusing sentence in intro

I can't quite figure out this sentence: "After some years, many of the people who have this subtype begin to experience neurologic decline without acute relapses as the secondary progressive subtype. "

I've spent several minutes here trying to write up what it might mean, without success. What is it that is the "secondary progressive subtype"? What is it secondary to? Are there other secondary types that are not progressive?

Call me confused. 24.39.174.1 (talk) 14:31, 24 January 2008 (UTC) That was me - I forgot to login. Leotohill (talk) 19:00, 24 January 2008 (UTC)

I'm going to remove that confusing clause and see who objects. Leotohill (talk) 19:01, 24 January 2008 (UTC)

The desription of the "secondary progressive subtype" is indeed accurate, as it is the usual consequence of un-treated RRMS. "Are there other secondary types that are not progressive?" Answer is No, but there are progressive forms that are not "secondary"....io-io (talk) 00:46, 10 March 2008 (UTC)

[edit] Bee Venom Therapy?

Im a little shocked that BVT (bee venom therapy) has not been brought up, especially considering the success stories with them.

Bee Venom Therapy at Discovery[1]

ODNation (talk) 01:54, 25 January 2008 (UTC)

A part of the article you mention: Given the fact that no major studies on BVT have been done so far: if there are no scientific articles on topic to mention it in the wikipedia article is not an option--Garrondo (talk) 09:06, 25 January 2008 (UTC)
I have found only one randomized trial in pubmed on bee venom therapy and multiple sclerosis and does not support its use. I have added this information to the article. Please next time search for credible sources before proposing editions.--Garrondo (talk) 09:33, 25 January 2008 (UTC)

[edit] doctor fabulini

A pennsylvania doctor has recently found a cure for ms that has not yet been widely accepted. He uses fluconazol and a 2 week no sugar diet to treat patients. He has cleared a whole wing of a hospital which dealt with MS by using this treatment. I am friends with one of his patients who could not walk but within a few months of seeing this doctor she went trick or treating with her kids

someone should post this —Preceding unsigned comment added by 141.152.238.229 (talk) 15:40, 25 January 2008 (UTC)

Sure...please provide facts... Miracles don´t exist but there is plenty of bussiness in trying to sell them.--Garrondo (talk) 15:51, 25 January 2008 (UTC)
After search on Fabulini: it does not even appear in google... not to mention scientific articles. Probably it does not even exist. Its the result of appearing in main page... I´m looking forward to ending this pain...agggggggggggggggggggggggg. --Garrondo (talk) 17:21, 25 January 2008 (UTC)
Well, you did want people to read the article, right? :) GeeJo (t)⁄(c) • 17:45, 25 January 2008 (UTC)

[edit] Disease-Modifying Drugs - Relative Efficacy

I propose the following:

1. A brief discussion on the Relative Efficacy of the disease-modifying drugs.

The article is informative about the difference of administration in the DMDs, right down to specifying the dosage intervals; it also goes into detail about the greatly-varying side effects. However, the article is completely silent on what is most important, which is the spectrum of what is cinically proven, and to what extent, and what is not. Instead the article states that all DMDs have been shown to be "modestly effective in reducing attacks and slowing disability progression" - which is in fact erroneous.

2. Deleting what is currently reference # 27, a page from the obscure "PeaveHealth" which is both obsolete and already inferior to the Wiki page. io-io (talk) 02:17, 27 January 2008 (UTC)

I agree on deleting ref 27. About the brief discussion on efficacy: there are proofs that all are effective or they would not be approved and its said that the two most efficient are mitoxantrone and natalizumab. If you want to provide more information find it and propose it here.--Garrondo (talk) 08:52, 28 January 2008 (UTC)
What I was referring to was the "slowing disability progression" part. I believe that both Betaseron and Copaxone, despite have ing been approved longest (and having the greatest opportunity), have NEVER proven in a placebo-controlled trial to have proven "slowing disability progression" - for example, from the Copaxone web-site, see the final statement - http://www.copaxone.com/NewlyDiagnosed/pivotTrial.aspx - this explains why Betaseron has declined chronically, as the other interferons are better - however Copaxone has no "threat" with few adverse effects, and so it thrives. Nevertheless, this information is central to the MS profile, a long-life condition for it's patients.io-io (talk) 00:33, 31 January 2008 (UTC)
Read first all refs: this ref is in the article and is from 2007. If you find something different in peer-review journals provide it.
Glatiramer acetate in multiple sclerosis: a review.Ruggieri M, Avolio C, Livrea P, Trojano M.
Multiple sclerosis (MS) is considered to be primarily an inflammatory autoimmune disease. Over the last 5 years, our view of the pathogenesis of MS has evolved considerably. The axonal damage was recognized as an early event in the disease process and as an important determinant of long-term disability. Therefore, the antiinflammatory and neuroprotective strategies are thought to represent promising approach to the therapy of MS. The therapeutic potential of glatiramer acetate (GA), a synthetic amino acid polymer composed of a mixture of L-glutamic acid, L-lysine, L-alanine, and L-tyrosine in defined proportions, in MS has been apparent for many years. GA has been shown to be effective in preventing and suppressing experimental allergic encephalomyelitis (EAE), the animal model of MS. GA has been, therefore, evaluated in several clinical studies and found to alter the natural history of relapsing-remitting (RR)MS by reducing the relapse rate and affecting disability. These findings were confirmed in open-label follow-up trials covering more than 10 years of treatment. The trials demonstrated sustained efficacy for GA in slowing the progression of disability. The clinical therapeutic effect of GA is consistent with the results of magnetic resonance imaging (MRI) findings from various clinical centers. At a daily standard dose of 20 mg, s.c., GA was generally well tolerated. The induction of GA-reactive T-helper 2-like regulatory suppressor cells is thought to be the main mechanism of the therapeutic action of this drug. In addition, it was recently shown that GA-reactive T cells produce neurotrophic factors (e.g., brain-derived neurotrophic factor [BDNF]) that protect neurons and axons in the area of injury.PMID: 17627671 [PubMed - indexed for MEDLINE]
--Garrondo (talk) 08:44, 31 January 2008 (UTC)
I have indeed checked references. I am well aware of the Argentina paper. However the statement "The trials demonstrated sustained efficacy for GA in slowing the progression of disability" is not a science-based conclusion, as you will see that it was an open-label trial - all patients got Copaxone, and no control to compare disability against - "These findings were confirmed in open-label follow-up trials covering more than 10 years of treatment".
Instead what is happening is that some of the patients have to quit their free-of-charge drug due to relapse and probably advancing disability. This makes for a favorable comparison between the lucky MS patients who appear to be faithful against the unlucky who appear to be unfaithful to Copaxone - http://www.ad-hoc-news.de/Aktie/en/12717760/News/13687362/Long-Term-Study-Shows-COPAXONE(R)-Significantly-Slows - and so they get some poor hospital (Argentina, Czechoslovakia) every year or two to publish the same comparison, where remarkably the effect on relapses and disability progression appears to actually increase all the time. Instead it's an unethical scam, as it uses the less fortunate MS-ers as the comparison to the ever-smaller group of surviving Cop users. Of course the world media picks it up, and reycycles it over.... that's how it goes.... of course it's not Teva DIRECTLY making the marketing claim.
You will not be able to find a standard controlled trial where Cop delayed disability progression, just a lot of noise.io-io (talk) 02:38, 1 February 2008 (UTC)

[edit] Relative effectiveness

After some research, and still some more to do for some of the minor scores, here is the "RELATIVE EFFECTIVENESS" table I was proposing to add. I would welcome ALL comments (from ANYONE) before doing so. . Thank You.
RELATIVE EFFECTIVENESS OF APPROVED DISEASE-MODIFYING TREATMENTS FOR MS
Medical Name Brand Name Safety limits long-term use Dosing Schedule Lesion Reduction Advantage (2 years) in Lesion Reduction Relapse Reduction Advantage (2 years) in Relapse Reduction Disability Progression Reduction Advantage (2 years) in Disability Progression
Glatiramer acetate[1][2] Copaxone No 1 x day subcutaneous injection Yes Vs placebo Yes 29% vs placebo No n/a
Interferon beta-1a[3] Avonex No 1 x week intramuscular injection Yes Yes 29% vs placebo Yes 37% vs placebo
Interferon beta-1a[4] Rebif No 3 x week subcutaneous injection Yes 80% vs placebo Yes 27% vs placebo Yes Vs placebo
Interferon beta-1b[5][6] Betaseron/ Betaferon No 1 x 2 days subcutaneous injection Yes 80% vs placebo Yes 34% vs placebo No n/a
Mitoxantrone[7] Novantrone Yes 1 x 3 months infusion Yes Vs placebo Yes Vs placebo Yes Vs placebo
Natalizumab[8][9] Tysabri No 1 x month intravenous infusion Yes 96% vs placebo Yes 68% vs placebo Yes 54% vs placebo
Comments Received on my TALK page (from Garrondo) which will be incorporated -

::Wow...you have done a great work. It´s a great improvement to the article. I only have some minor improvements:

*I don`t like the colur use, specially the blue for letters, since they seem internal links. I would rather prefer black as in all articles. Yellow might also be too strong

*I would add internal links to medications, type of injections, and any other word difficult to understand

*I would also writte completely sub-cutaneous, since just sub-c would not be understood by some non medical readers. DONE

*I would eliminate the "?" after safety limits... In no other title you have added it. DONE

*I suppuse v is versus. Im not english, but, is it not better understood as vs? DONE

*Interferon 1-b is betaseron in US, but betaferon in all Europe, both names should appear.DONE

*Add all the refs with diberris tool: http://diberri.dyndns.org/wikipedia/templates/ to continue with the format used in the articleDONE

All Other Comments and/or Input (some data is sitll missing) by Anyone are most Welcome.... io-io (talk) 15:06, 4 March 2008 (UTC)

Other changes done:

  • simplification of the titles
  • Same use of mayusc along the table.
  • Brand names in italics

A question: are quantities at relapse reduction really needed? --Garrondo (talk) 10:43, 7 March 2008 (UTC)

Thanks - those changes are great! The quantities of relapse reduction have been for many years the normal "primary endpoint" of MS trials (it used to be just lesion counts, but they are difficult to measure perfectly and the correlation with clinical benefit is not great), as it was previously thought that 2 years might be a tough time-frame in which to prove an advatange in limiting disability, which is of course the "primary issue" with MS...io-io (talk) 00:17, 8 March 2008 (UTC)
Hi io-io, I know nothing about pharmacology etc , and I realize that you have done a look of work on this. I do however wonder if this level of detail in necessary or desirable in an encyclopedia entry. Is it the sort of thing mooting at various medical and pharmacology project pages, just to see what others think? Maybe it is just me. I am quite happy to be overruled --Slp1 (talk) 23:01, 7 March 2008 (UTC)
Hi Slip...you will see if you scroll up that this discussion was started in January, and the table borne out of it - I mean why compare side-effects and administration route, if not efficacy...especially when MS patients are be-set with all sorts of nonsense about therapies ranging from nutrition and zen to stem-cell treatments in 3rd-world countries...in fact all DMD drugs work to some extent, it is established...io-io (talk) 00:17, 8 March 2008 (UTC)
I think that treatment of multiple sclerosis is alredy an specific article, (there is alredy a multiple sclerosis general article) so information can get to much more specific level of detail. The difference about the different treatments are really difficult to explain so a table like this one is the best method from my point of view to give this information. The main aim is not to give information for medical workers (and thats the reason why I eliminated the quantities of product given) but to give information for a general reader (who of course would be probably very interested in MS due to different reasons) on the efficacy of the different medications. I think its a good improvement to the article.--Garrondo (talk) 10:03, 8 March 2008 (UTC)

I have not done the research so I don´t know if this is absolutly correct, but maybe a way to simplify the table was only to put the long term comparisons against placebo. It would look something like this. What do you think (Specially io-io)? --Garrondo (talk) 10:27, 8 March 2008 (UTC)

Yes this is indeed much simpler and better. Maybe instead of "No" we should write "No Proof" or "Un-Proven" or simply "Not Shown". The reason I had earlier specified a dosage strength for Betaferon and Rebif is partly in strict conformance with the trial results, and partly because a higher dose for Rebif (44mg) is available, but is only occasionally used (poor tolerability and risk to liver) - and I know that it's scores were almost identical to the main 22mg dose anyway, so it hardly matters. Your choice of colours is also appropriate to the tone. I have not had much time to edit Wiki (I want to research the missing scores), but will perhaps this evening or tomorrow. Thanks again....io-io (talk) 16:29, 8 March 2008 (UTC)
No need to give thanks... You have been the one doing the hardest job. I proocceed to say "Not shown", and of course it can be improved with your research of the missing scores... but right now I believe its good enough to load it to the main article and improve it there... Feel free to do it. The honour of doing it should be yours. :-) --Garrondo (talk) 17:22, 8 March 2008 (UTC)
EFFECTIVENESS COMPARISON OF APPROVED DISEASE-MODIFYING TREATMENTS FOR RELAPSING-REMITTING MS
Medical Name Brand Name Safety Limits Long-Term Use Dosing Schedule Results after Treatment for Two Years Relative to Placebo
Improved Relapse Rate Reduction Delayed Disability Progression
Glatiramer acetate[1][10] Copaxone No restriction 1 x day

subcutaneous injection

 29% Not shown
Interferon beta-1a[3] Avonex No restriction 1 x week

intramuscular injection

 18% 37%
Interferon beta-1a[4] Rebif No restriction 3 x week

subcutaneous injection

 29%* 22%*
Interferon beta-1b[5][6] Betaseron / Betaferon No restriction 1 x 2 days

subcutaneous injection

 31% Not shown**
Mitoxantrone[7] Novantrone Yes (absolute max 3 yrs) 1 x 3 months

intravenous infusion

 67%*** Yes***
Natalizumab[11][12] Tysabri No restriction 1 x month

intravenous infusion

 68% 54% 
Notes -
*Results are shown for the 22mg or most common dose of Rebif
(interferon beta-1a). Results for a 44mg dose, which is less well 
tolerated, were not significantly better.
**In RRMS, interferon beta-1b has not proven that it can delay
disability progression. However, in SPMS, it has proven that it cuts 
the risk of disability progression by 16% over 2 years.
***Most patients in the mitoxantrone trials were SPMS, not RRMS. In 
a trial with some RRMS patients, it did achieve a proven advantage in 
relapse rate reduction of 67%, but did not use the same measures of 
disability progression. In the sum of trials with mostly SPMS and PRMS 
patients it did however show cuts the risk of disability progression by 
66% over 2 years.
Finished data, added explanatory Notes...important to distinguish between RRMS and its "later" or advanced form SPMS in data, as this largely defines actual treatment use....io-io (talk) 00:39, 10 March 2008 (UTC)

After looking up various trials and labels, I decided to eliminate the column for "lesion reduction", for 2 reasons. First, the various trials soemtimes report total lesions, and others report only "gandolonium-enhancing" lesions", and it does not seem possible to give a consistent numerical category. Second, it is not a "clinical effect", only an MRI measure, and only moderately correlated with patient perception and outcome....Also I improved column-widths, to increase the importance of the efficacy comparison itself (last 2 columns).....io-io (talk) 21:59, 9 March 2008 (UTC)

[edit] last version table

I prefer this design

This is maybe the best we can do - I had been trying, not to make the rows deeper, but to make the 2 efficacy columns wider, at least relative to the dosing schedule column, which was looking very wide. Hmmm...perhaps we could add back a "lesion reduction" column and simply put "YES" in each box...But in any case, I agree that we don't want to make the box any "deeper" (longer) than it is now.....io-io (talk) 13:52, 11 March 2008 (UTC)
I agreed with you when you eliminated the lesion reduction column and I don´t think there are any problem on dosing schedule being widther than other columns (at least is much prefereable to rows becoming deeper. Right now as I alredy posted in your talk page the only thing to do is to add the references you name in the notes section to its corresponding comment. --Garrondo (talk) 14:30, 11 March 2008 (UTC)


EFFECTIVENESS COMPARISON OF APPROVED DISEASE-MODIFYING TREATMENTS FOR RELAPSING-REMITTING MS
Medical Name Brand Name Safety Limits Long-Term Use Dosing Schedule Results after Treatment for Two Years Relative to Placebo
Improved Relapse Rate Reduction Delayed Disability Progression
Glatiramer acetate[1][13] Copaxone No 1 x day subcutaneous injection 29% Not shown
Interferon beta-1a[3] Avonex No 1 x week intramuscular injection 18% 37%
Interferon beta-1a[4] Rebif No 3 x week subcutaneous injection 29%* 22%*
Interferon beta-1b[5][6] Betaseron / Betaferon No 1 x 2 days subcutaneous injection 31% Not shown**
Mitoxantrone[7] Novantrone Yes (max 3 yrs) 1 x 3 months intravenous infusion 67%*** Yes***
Natalizumab[14][15] Tysabri No 1 x month intravenous infusion 68% 54%
Notes

+Results are shown for the 22mg dose. Results for a 44mg dose, which is less tolerated, were similar[16].

++In RRMS, interferon beta-1b has not proven that it can delay disability progression. However, in SPMS trials, it has been shown to cut the risk of disability progression by 16%[17].

+++Most patients in the mitoxantrone trials were SPMS. In a trial with RRMS patients, it achieved an advantage in relapse reduction of 67%, but did not use the same disability progression measures. In the sum of trials with SPMS and PRMS patients it did cut the risk of disability progression by 66%[18].
Great - exactly what I was trying to do in the first place, but my asterisks (*) were turning into bullet-points...we can probably put it on the Wiki tomorrow....io-io (talk) 21:00, 10 March 2008 (UTC)


[edit] Limits to Disability Progression

Limits to Disability Progression claims for these treatments is disputed - some of the referred articles are very old indeed (1995 & 1996 i.e. before proper disclosure rules were introduced and when beta interferon treatments were extremely new). Many professional neurologists would not subscribe to these evaluations. I think one has to be very cautious when claiming that any of these treatments limit disease progression especially in view of more recent meta-studies that dispute such claims, particularly in the case of the interferons (see Cochrane reviews). Additionally, natalizumab is a very recent drug with too little data to clearly establish whether it limits progression. Conventional MRI has been shown to imperfectly represent disease activity and yet, in these earlier studies, is taken as a definitive bench-mark. One of the other quoted texts is an expert opinion and not a study. I wonder why one particular editor has been so determined (for some little while) to show the efficacy of these treatments against progression. One has to be careful of (undisclosed and undectable) conflict of interest in Wikipedia articles, which are not subject to the same rigour and professional criticism as medical articles. Ultimately, patients are the ones making important and expensive decisions as to whether to undergo these drug regimes. Wikipedia is very high on the search engines and has a duty to present impartial information - it is the reponsibility of editors (both professional and amateur) to police this. Often that means checking the references. Better still, I believe that Wikipedia should desist from addressing drug treatments for multiple sclerosis - there are better and more rigorous sources. If editors do conclude that Wikipedia is a valid forum for discussion of treatment efficacy then I believe that proper and rigorous checks and balances are introduced. Laetoli (talk) 08:04, 10 April 2008 (UTC)

Interesting, but before I comment, who is this "one editor"? io_editor (talk) 23:36, 11 April 2008 (UTC)
I am about to remove the "limits disease progression" claims for the interferon betas. This has not been adequately shown. The cited refs are very old indeed, 1995, 1996, 1998 etc or are label info. The modest anti-disease progression claims made by these studies are disputed because drop-outs of disease progression subjects were not controlled for. One of the studies says "Longer-term benefits may become clearer with further follow-up and investigation." This is NOT evidence that they protect against disease progression. I cannot find more recent study data that overturns the conclusions of these meta studies: Cochrane reviews, which show the interferons to only have proven benefit against relapse rate and unproven against long-term disease progression. The analysis of glatiramer acetate shows it to be statistically ineffective even against relapse rate. Laetoli (talk) 10:10, 10 April 2008 (UTC)
While waiting for you to come back, I disagree with most of what you say - although I have sympathy with one thing you did - placing the "Warning" on the page - it was removed, and I have 2 suggestions (to be talked about) - 1) placing it on the DRUG pages (not just MS) because NO patient with a serious progressive and disabling disease should be frightened away from a DMD - because a DMD is the ONLY thing that has hope (won't work in all, and works to widely varying degrees) in tackling the underlying pathology
The idea that take anything because it MIGHT work is the most irresponsible thing I have yet read on Wikipedia. Inf-B acts against inflammation. There is certainly inflammation in MS and that might contribute to the severity of a relapse. That might be in a mechanical way and evidence would suggest that dies back with remission. There is no evidence that inflammation causes transection nor oligodenrocyte apotosis. Indeed, to the contrary there are several pieces of evidence that a third, as yet unknown, agent causes the inflammation, axonal transection and oligodenrocyte apotosis. We have to be very careful - our job is NOT to oversell these drugs with their far from benign health and cost profiles. Laetoli (talk) 11:25, 15 April 2008 (UTC)
Bear in mind that around 60% of PwMS can expect a normal life-expectancy. This is a disease of several decades - this is not ALS. Laetoli (talk) 11:58, 15 April 2008 (UTC)
- and 2) maybe thenthis I thought was a responsible approach....io_editor (talk) 02:24, 15 April 2008 (UTC)
I'm preparing a fuller objection. You'll have to wait a day or so. However, in the meantime, I'll draw your attention a quote from one meta-study/review, which post-dates the quoted studies from the table: "Interferons can help to reduce disability and attacks for people with multiple sclerosis, but there is not enough evidence about their usefulness in the long term."Interferon in relapsing-remitting multiple sclerosis The same study criticised the methodology in the same studies: "Although seven trials involving 1215 participants were included in this review, only 919 (76%) contributed to the results" and "If interferon-treated participants who dropped out were deemed to have progressed (worst case scenario) the significance of these effects was lost (RR 1.31, 95% CI 0.60 to 2.89, p = 0.5)." IMO, and many other observers including the reviewers, this is fatal to a conclusion that Inf-B delays long-term disease progression. As things stand, the long-term effects these treatments has still to be proven. Worse than this, from a patient's perspective, long-term disease progression is the most important goal of any treatment. Riding out relapses is not so hard - permanent disability is. Laetoli (talk) 11:25, 15 April 2008 (UTC)

It seems to me like the main issue is with the table in the 'Relapsing-remitting MS' section, which has specific data on percentages for reducing relapse remission and limiting disease progression. The table is the result of talk page discussion (see the preceding two sections), so this third section is now effectively extending that same discussion, eh? ;-)

It is clear that a lot of work has been put into the table, and I think that looks very good. However, I do have to question whether this falls under original research. Because it appears to me that the table is not published in its entirety in a single source, and rather, pieced together from multiple sources. And that is great from the perspective of an author(s) writing a review article for a scholarly journal or something, but that's not what wikipedia is for. The biggest issue I see with the data in the table is that, with data coming from multiple sources like this, trying to establish reasonably accurate measures for relapse rate and disease progression is going to be very difficult, and quite possibly wildly inaccurate from a statistical standpoint as well. In order for these statistics to be even close to believable, far more information on the studies conducted is needed, as there are far too many factors involved here that could throw off these percentages. If the table in question was all from one source, we could put it in and cite that source, and individuals interested in the specifics of the study could click on that to read it if they want. But as it stands, a table that's been concocted from multiple sources with details of said studies that are unclear,... I've got to call WP:OR on this one. Dr. Cash (talk) 21:23, 14 April 2008 (UTC)

But ALL Wiki articles come from multiple sources. There is no WP:OR there. What factors could "throw off the percentages"? The FDA and EMEA review trial makeup rigorously and do not accept biased protocols.io_editor (talk) 00:41, 15 April 2008 (UTC)
Hmmm. What could throw off percentages? Where does one start? There are so many published studies with deep statistical flaws, I don't know where to begin.Laetoli (talk) 11:25, 15 April 2008 (UTC)
In wiki we are no judges of article quality. If an article appears in a quality peer-review journal it is acceptable. There is no problem either from my point of view in creating a table from multiple sources (Wikipedia is precisely that: a review from multiple sources.) Most tables in articles are created by editors and as long as any different source used is clearly stated is not OR. However if the controversy is on the efficacy of some treatments and we have references that state different or null efficacy rates then the solution would be to include such reference in the table and state in the table the efficacy variations (something like "0 to 20%"). --Garrondo (talk) 12:14, 15 April 2008 (UTC)
This is not a game, Garrondo. You are talking about what people put in their bodies and take out of their wallets. As this text is near the top of SE rankings, it is read by many people with MS. What you are trying to say does not reflect what evidence-based medical science says. Assuming that no one here works for a pharmaceutical company (and I have my reservations) we have a duty to reflect that science, otherwise we will be advising them poorly. A group of highly-respected neurologists with full access to the same data and using SOTA statistical packages have concluded that these drugs were not proven to delay disability progression. Another group of professional medics, the National Institute of Clinical Excellence, reached the same view based on the same studies and also concluded that INF-B was not effective in this manner. You, on your own, have tried to replicate their work and have reached the opposite opinion. You must get your work published in a peer-reviewed journal before we can quote it. In the meantime, it MUST be removed. Laetoli (talk) 16:18, 15 April 2008 (UTC)
As I indicated early on on this talkpage, I have long had my doubts about this table. The more I look at it, the more doubts I have. Simplifying complex treatment efficacy research from multiple independent studies to "percentage Disability Progression", "percentage Relapse Reduction" ignores the many, many other variables that may affect these results, including differences in how each of these were measured and evaluated and differences in the subjects (age, stage of disease etc etc). And as we all know, using means rather than ranges is often very uninformative and even misleading. Is there actually any statistical significance between these results? Who knows, and it certainly isn't for us to do, but it certainly isn't appropriate that we imply that Natalizumab is the winner, which seems to be the implication to this lay editor, especially given the evidence provided by Laetoli that contradicts the table.
I am going to address Laetoli's evidence, which is largely based upon the Cochrane reviews of Interferons. And the "implication" that you see is not some kind of a fringe falsehood, as N proved its efficacy targets to p-values with a few zeroes after the decimal, such that subsequent articles cannot hope to claim "no statistical aignificance" as they have done with the others (Novantrone excepted). However efficacy is not everything, and in fact of the 3 main classes of MS drug, the side effect profile is (unfortunately) inversely related to efficacy, and currently it would appear that the neuros chose to treat naive/presenting patients according to symptoms and MRI.io_editor (talk) 17:10, 16 April 2008 (UTC)
I think there are enough significant concerns from Laetoli, Dr. Cash and myself, that the table should be removed until there is consensus that it is an appropriate addition to the article. I take seriously the view that we must not mislead the lay public on this matter. Perhaps there are ways of modifying the table, as mentioned by Garrondo, that will help to satisfy concerns, but until that happens I believe it is appropriate that the table be removed. Slp1 (talk) 22:35, 15 April 2008 (UTC)
I won't fight against it. Although I still think there are ways to improve it and those that eliminated should try to do it. Nevertheless, once it has been eliminated I'm going to get rid of the message on neutrality.--Garrondo (talk) 14:09, 16 April 2008 (UTC)
One more thing: those that have eliminated it, please at least fix the citation problems you have created. I don´t have time right now and you are responsible for it (and nobody would do it otherwise)--Garrondo (talk) 14:12, 16 April 2008 (UTC)
I apologize for the citation problems, and have fixed them. I should have checked. I'm afraid that I don't really agree that it is up to the people who argued for the removal of the table to try and fix the fairly fundamental problems with it. How do you fix original research and inappropriate comparisons between independent studies? If editors want the table in despite this then it really is up to them to propose something that will achieve WP:consensus here on the talkpage: "The burden of evidence lies with the editor who adds or restores material" (see WP:V). Note that above, I did not rule this out as a possibility. Slp1 (talk) 14:52, 16 April 2008 (UTC)
By what standard should it be removed BEFORE there is consensus, before there is discussion? Sure it takes a nano-second to delete. It took many, many hours to develop, during which it was on the Talk page (and before that, on my beautiful User talk page) for close to 2 weeks.
See also my remarks inserted above. User:Laetoli may feel strongly about this, but his fall-back on "evidence-based medical science" - consisting of the Cochrane Reviews which lumped various studies post-hoc into an amorphous ball - is by definition inferior to the clinical trial results, as these were all prospectively pre-planned. I am writing something further, in detail, about this.io_editor (talk) 17:10, 16 April 2008 (UTC)
By this standard WP:BOLD, by this standard [2] and by this standard "The burden of evidence lies with the editor who adds or restores material" (see WP:V). Your work is not lost, as of course you know. Could you explain a bit more about this edit [3] which talks about a conflict of interest that you have regarding this website, [4] which is a website following some patients taking Natalizumab? I apologize if I have misunderstood your reference there, but would like to understand your situation better.Slp1 (talk) 21:33, 16 April 2008 (UTC)
Ok, my evidence is coming up. I see you personalize the matter, and that's fair enough given my beautiful talk page (which you visited when you wrote there - I really should archive this crap). Here is the context - this was my very first edit on Wikipedia, and the last sentence (only) led immediately to a COI from User Antelan, who I will not characterize, but who repeated it recently on the N page and then on my Talk page for good measure, and then expects us understanding. So those words you are looking at are an expression that, just like Laetoli, I am most interested that MS patients get the best information, and I have researched in areas peripheral. I have no association with that site - I wish I had - it is NOT a Tysabri site, but it is the MSRC or MS Resources Centre of the UK, 1 of the 2 main UK sites (that I know of) where MS patients in droves visit to find information - this one page is one of hundreds there and it is an independent charity organisation, well-staffed nevertheless, and much more than a "web-site". So basically I was telling Antelan that I was interested fundamentally in MS and MS patients and MS treatment, because despite dozens of contacts with this User (including edits and deletions that I find represhensible), Antelan has never demonstrated the slightest such interest, or even any understanding or even sympathy beyond what you can read in the newspapers (it looks like I characterized the User after all; well sometimes they get to me). By the way, these long-timers here have their friends, and if there is a parallel to this table, it is on this page, which should get enormous attention in the years ahead long after I am finsihed with WIki, and you can see on that Talk page that the same accusation turned up from a long-timer - even though there are absolutely zero DMDs to advertise in Alzheimers, not until 2010, and that's if a break-thru happens soon, which most doubt. Actually I became famous then on Talk WikiMed, I do hope you enjoy the replies with one of the AD editors there who compounded the COI suggestion with another one of extensive "bad grammar".
I also wanted to address where you pointed out here that there was an "implication" from the table that natalizumab (N) is the most effective drug. Well apart from novantrone, that is de-facto the widely-accepted truth, and there has always been a statement on this page with a 2007 paper referenced which speaks to that very conclusion. However N has other issues, not least being a media darling of alleged FDA bungling (which is BS) on safety issues, which appear almost nebulous despite the facts. And so yes I feel conflicted because the whole paradigm around N (and this about MS therapy) is screwed up; (for example it is simple and legal for competitors to "hint" that their drug does not have a certain well-known side-effect) - and the MS patients do not have TIME on their side, and their visible problems are surpassed by problems not visible. But also I wanted to say is that COI and drug company allegations are themselves insulting because #1 you need to have an interest in something in order to know it in depth; #2 it is tempting to assign a COI, if the accuser knows less on a select subject, and there is nothing much that the accused can do, as their own edits condemn them; #3 do you really think that no-one on these pages does not own shares in some drug company or technology company or other business company; and #4 I have been to the Stem Cell Transplant page, and once I started to edit there I feel like the resident authority, because up to now it was written by romantics or pre-meds at best.
However, Laetoli's problems are more with the interferon drugs, by far the market leader as a group, and of course N's biggest competitor, but I would absolutely insist that they work too to some extent, the evidence is in fact fairly consisent in defining their benefit. Whatever anyone can say about the drug companies (most of which may be deserved, as the vast majority of their income as a whole comes from routine medicine cabinet stuff), most definitely the best hope for MS and Crohns too will always be the "next" DMD in the pipeline. In human history, there has never been a better time to have a serious progressive disease, thanks mainly (but not solely, as I bet Garrondo knows!) to DMDs; hopefully even better drugs will be found to make that distinction absolute. I think I have written too much, there must be several things here to get stoned about, but I am known to insert foot-in-mouth.io_editor (talk) 23:46, 16 April 2008 (UTC)
Okay, thanks for the clarification of the COI remark. I appreciate it.--Slp1 (talk) 16:58, 19 April 2008 (UTC)

to: Laetoli - OK, using up all the ammunition now, because I will be away for a day - now I will address what User:Laetoli wrote, under separate sections. I already told him that I was most sympathetic to the other action he took - putting a big WARNING up on Drug pages because anyone can edit and skew a Med article here, and that medical advice should be sought elsewhere - because reality IS that some small percentage of patients who have long-term therapy choices in front of them WILL read these various drug pages and will be influenced by what they read. However, the reason the page started is that it appears ridiculous that, with today a fairly large of treatment choices, and with the fearful side-effects and unpleasantness shown in relative comparison, then at least the regulatory efficacy numbers should be compared too. After all, the #ONE thing a patient wants taking a Drug is efficacy. But more about numbers later.

because it MIGHT work - Laetoli, you didnt answer my questions, but you write "take anything because it MIGHT work is the most irresponsible thing I have yet read on Wikipedia" - well I didnt say "it MIGHT work" at all - I was sensitive to the problem that they dont work for some patients (in fact for many, it is NEVER known if they helped to some degree, because relapse rates vary and are intermittent), as you can see from what I wrote. But in FACT this is the case with ALL these serious progressive diseases - there is no cure, and the very best drugs do NOT have a uniform result, nor close to it. Take Hepatitis C for example - the drugs are awful, and for 50% it's almost a cure, and the other 50% simply go back to the end of the line. In fact more so for Hep C than MS, "it might work" is the cruel paradigm.

Neurologists - you write that "Many professional neurologists would not subscribe to these evaluations" - and yet you base your evidence on the Cochrane reviews, written by a handful. And what do they the Cochrane reviewers do in their practices, do you think they refuse to prescribe DMDs? The fact is that in the USA, some 70% of MS-ers are on one of these DMDs, and probably another 15% are off them only because they failed them. In the EU, the percentages vary wildly between the countries, I think I saw that in Sweden it may be 75% and in Poland 1%-3%. But these numbers show that in the developed countries the overwhelming majority of neurologists DO prescribe DMDs to their patients.

Patients - #1 - I noticed from your first ever entry your remarkably accurate comment that MS patients have "a lot on their hands" - I could not have said it better. To compound matters, upwards of 50% have cognitive issues to some degree, which can unfortunately mean that the potential for adverse effects (which the doctors MUST tell them about) is the over-riding concern. If you had MS, you too would be faced with the same fear, and would want to know what are your chances, as the adverse profile (anything from the drudgery of daily injections to PML) will be fully explained. Therefore my view is that, for the inevitable number of MS patients who look on these pages at the very moment that they have been presented with treatment decisions, that they get a perspective on the MAIN issues - you can already see on the page that side effects get 20 lines or so - are side effects the main issue. Absolutely not, and you said it yourself, it is Disability (and it's pre-cursor, Relapse Rate). So for those who still have a wide choice, information and balance is vital.

Patients - #2 - I dont know where you are (UK I assume, given your NICE cites) but the consensus among MS patients is absolutely make the DMD choices available, and THEY and their doctors will decide. Two examples - in the UK, after the NICE negative evaluation (effectively a Government-paid consultant) of interferons and copaxone, such was the outcry from MS patients that eventually the NIH had to do a U-turn - now generally they are FREE to MS-ers. Another obvious example was in the USA where natalizumab was before a Public Hearing, and such was the fear among MS patients that the safety-obsessed (ie politically-pressured) FDA would prevent its return, the planned couple of hours of "public testimony" went for a full day, forcing a second day of hearings. Once again, your patients DO want to know, and DO want better drugs.

Patients - #3 - Cost – You speak several times to the patients’ pockets, etc, but I believe this is the least important factor. Overwhelmingly in the developed countries the patients do not pay for these drugs at all, or at most, a small percentage. Even for patients in the USA who have no insurance, there are programs whereby they can get them. Finally, there is little difference in cost between the drugs (with the possible exception of novantrone, which is an older chemotherapy drug).

"evidence-based medical science" - This is where, in my opinion you are technically wrong in a way that has impressed others here, but unduly:

  • The numbers - these were not incidental to the trials - they were the primary and main secondary design TARGETS, the whole INTENT of the trials. In fact "evidence-based medical science" is based primarily upon prospectively (up-front) designed clinical trials, and not retrospective reviews of studies bunched together - which unfortunately are what the Cochrane reviews are. I am not at all saying they are junk; what I am saying is that they should be 2nd tier to the "designed" studies..
  • I also pointed out to you that ALL Wiki articles come from multiple sources. Yet in your edit description, you described your deletion as one of removed "aggregated" data. There is ZERO aggregation in the Table, it is just a list with the real numbers taken from the official regulatory labels.
  • Once again, I respect the Cochrane reviews - in fact however, it is THESE reviews that "aggregate" results from several trials! Why did the Cochrane reviews get worse results? I suspect that some of the interferons were tried in much tougher SPMS, and the results degrade the overall total. We can look.
  • Getting back to the numbers - and yes some of the data is old, and the trials then were looser than today - but at that time, those were the RULES. It is like saying that GWB should not be President, because he lost Florida - but like it or not, the rules ended up supporting him.
  • Again - the numbers - these were not incidental to the trials - they were the primary and main secondary design TARGETS – the whole INTENT of the trials. What happens was that, they knew the FDA and EMEA rules of the day, and they had an idea from Phase I and II how their drug would fare, and so they statistically designed the trial size knowing the probability basis. And ALL of these key trials succeeded (5 or 6 total for 3 interferons); it is no coincidence. It seems the rules then did not have to exclude drop-outs. No-one likes that now, but if they were trying today, they would simply have much larger trials, and in which case the same advantage would be statistically significant (the larger the trial size, the easier to show this).

Finally, I want to point out to you that, as you said, the most important issue to an MS patient is Disability Progression. Certainly two of the drugs have had over 10 years to prove a Disability advantage, and yet they have failed to do so - I think that it is quite OK if that shows up, because the oldest drugs have had the most chances; but the other interferons have also succeeded to the design standard of their day-at-court. When I first saw this page, I thought that both what the DMDs can do, and what they relatively achieve, were lost on the page. I believe MS patients are looking for Efficacy as the #1 priority – that is why I made the Table. Original idea? Well I don’t know, there is that paper I referenced. Original research? Not at all, it is basically a list of numbers, the official numbers too, and all RRMS.io_editor (talk) 03:19, 17 April 2008 (UTC)

Wow! There is certainly a lot to reply to here!
First off, I realise that I have offended a few people for which I apologise unreservedly.
My doubts are not solely with the interferons. However, Wikipedia is not a forum that allows for the expression of personal beliefs and we must stick to the hard and fast rules of evidence-based medical science, which, incidentally, in my opinion and in reply to Garrondo, doesn't mean that every published article is acceptable. For example, in 2002 Dr. Christopher Hawkes ref published an article in the The Journal of Neurology, Neurosurgery, and Psychiatry (peer-reviewed) alleging that MS might be sexually transmitted. This flew in the face of a number of well-conducted studies and was rounded discredited in both the press and in a number of professional articles. To rehash Hawkes' hypothesis on Wikipedia would be irresponsible and misleading despite the fact that it's possible to cite a supporting peer-reviewed article. If we are going to cover this subject properly then, yes, it is our job to judge the quality of articles.
I'd like to make a broad and long point on the Disease Modifying Therapies (DMDs) in reply to Io_io_editor for the purposes of this discussion only - please bear with me - it is a point of view only.
1) Trial evidence suggests that none of the DMDs are particularly effective at slowing disease progression. They are great at reducing both the number and severity of relpases and, perhaps, a slight suggestion that they might help a little with progression but nobody is shouting "Cure!" just yet. Why not?
2) The initial study of another Monoclonal Antibody (Mab), Campath-1H, on people with secondary progressive with relapses MS by Compton and Coles in Cambridge was disappointing.ref The drug completely eliminated relapses from the trial population but failed to slow progression at all. Campath-1H kills T-cells by binding to their surface proteins and trial subjects' T-cell counts fell to nearly nothing, which ought to mean that T-cell mediated autoimmunity whould fall dramatically as well. But progression continued. Why?
3) Reseach on clinical and pathologic (tissue samples) findings in 12 patients showed that oligodendrocyte cell death preceded inflamation in MS attacks. ref Some, e.g. Pender ref, have suggested that this might be because steroid infusions cleared all the T-cells from the area but the authors refuted this and a more convincing account of caspase mediated or other oligodendrocyte apotosis has been put forward by others, e.g. ref
4) Diffusion tensor imaging and other advanced MRI techniques have shown that Wallerian degeneration occurs during relapsing-remitting as well as in secondary progressive MS in the absence of inflammation, e.g. ref How can this be if MS is an autoimmune disease where the damage is done by inflammation?
There is other evidence on both sides and, of course, it is well-known that inflammation accompanies MS relapses. The point is that limiting inflammation either by steroids or DMDs does not effect a cure nor even substantive reductions in disease progression and it’s beginning to seem unlikely that it ever will. The bigger question is why so many research dollars are being thrown at inflammation-limiting strategies?
All the DMDs have adverse side-effects. Some are milder than others but simply having to stab yourself everyday presents a substantial reduction in quality of life. Many people with MS use DMDs, some paying for them out of their own pockets, and many do not realise the paucity of evidence that they will delay the time until secondary progressive. Indeed, a young woman I talked to yesterday thought that they had been shown to do exactly this.
I'll reply to your other points later. Laetoli (talk) 11:58, 17 April 2008 (UTC)
Your knowledge on mechanism-of-action theories far exceeds mine. As you know however, it is the macroscopic issues that count to the patients, and indeed today it is those issues that the clinical trials are designed to target (Betaseron, being first, got an easy ride). I want to come back to that later, but one thing that caught my eye was your remark that "simply having to stab yourself everyday presents a substantial reduction in quality of life" - I could not agree more. In fact the precent of MS patients that have been steadily on the same DMD for say, 5 years or more, is remarkably small, due in part to the fact most of them are not long available, and because of the modest efficacy, side effects - in particular depression due to interferons - and so on. When I saw this video (MSIF conference, Czech Republic, Oct '07), where this well-spoken 22-year old woman has already twice come to a dead end with her injections, I get the unmistakable impression that there is no way the patients can keep compliance up indefinitely into their 30s, 40s, 50s, 60s. And in her case, she only had Avonex, which is once-per-week.io_editor (talk) 17:04, 18 April 2008 (UTC)

I will leave others to discuss the ins-and-outs of these drugs since it is all beyond my ken. To me, however, the key issue is the way that individual studies' treatment efficacy results were presented, and in fact 'compared' inappropriately in a table. By way of explanation I will give an Wikipedia example from my own field.

An editor, who incidentally had a COI, made this edit [5] giving percentage reductions in stuttering following 3 different kinds of treatment: Treatment A 48%, Treatment B 63% and Treatment C 71%. Makes it look like Treatment C is the best, right? The thing the editor didn't report was that the studies repeatedly said that the differences between treatments were not statistically significant. He took actual facts from the study and synthesized them together to prove a point of his own. In this case, all the treatments were offered within the same study, the subjects randomly assigned to treatment groups, exactly the same measures of outcome used etc.

In the case of these drugs we have multiple different studies, likely with different ways of measuring outcome and with different subject pools. Presenting average 'improvements' is thus even more inappropriate than it was in the stuttering example above. It is original synthesis and contrary to these reliable sources guidelines [6]

How reliable a single study is considered depends on the field, with studies relating to very complex and not entirely-understood fields, such as medicine, being less definitive. If single studies in such fields are used, care should be taken to respect their limits, and not to give undue weight to their results. Meta-analyses and systematic reviews, which combine the results of multiple studies, are preferred (where they exist).

which suggests we should be using the meta-analyses and systematic reviews as the primary source of information here. Slp1 (talk) 17:25, 19 April 2008 (UTC)

Im actually very surprised that you could find such a source!
  • I think (that's all I can say, but I accept that wiki source you gave does not give any such context) the difference has to do with epidemeological studies - where you want to make the overall population size huge in order to check for killer side effects in routine-use/OTC drugs - this is how the Vioxx problem was found, and even that was controversial as to what had been proven or not.
  • I previously described above how trials are designed prospectively from the outset, and the results are the results. Usually each trial has a purpose, and usually for Phase IIIs they are in pairs (as is the case in MS today), and so the next trial has a different purpose, with some variation, be it small or large. So that then, years later, to go backwards you may not be mixing oranges and apples, but there your meta-analysis is not pure, From a biostatistical standpoint going back to look at such different (or slightly-different) trials leads the study open to suggestions of dredging or even http://en.wikipedia.org/wiki/Misuse_of_statistics#Data_manipulation worse], so it is normally frowned upon. I am NOT saying this was the intent of the Cochrane reviews, I am just supporting what I said before, that prospectively-designed studies are top of the hierarchy, and you usually need Two to get FDA or EMEA approval today.
  • I went to the FDA website and found its regulatory guidance on satistical principles for trials. Here you can find everything that each trial (or pair of phase III trials) has to conform to. On page 40 (pdf page 43) you can see how a meta-analysis might be useful as tool between trials of already adequate size; but see later for the definition of meta-analysis (upfront intent, etc). You can also easily find the other Trial Design Considerations - everything is forward-looking, nothing backward-looking.io_editor (talk) 19:51, 19 April 2008 (UTC)
Another argument against use of meta-analyses is that, per here (end of sub-section) the Power of a Trial to prove something depends on the Size. Therefore you could easily have 2 or even 3 failed trials, and perhaps they even had different primary endpoints (in MS this has ranged from MRI-evidence to Relapse Rate to Limiting Progression), and then you find that by merging them into a meta-analysis, that one of the important endpoints becomes statistically significant, even though the relative effect is much the same. So have you proved something to the standard of p<0.05 ? No, of course not, because you already failed a number of times. You are not allowed to keep rolling the dice until a "6" shows up.
At the same time, I have looked now at the Cochrane review of the interferons as a group - here. I have to say that it does not include any SPMS patients (I thought it would), and it's all placebo-controlled, etc. The only thing I can point to is that it makes an assumption "If interferon-treated patients who dropped out were deemed to have progressed (worst case scenario) the significance of these effects was lost (RR = 1.31, CI [0.60,2.89], p = 0.5)." In interferons however, as the writers themselves say "Because of prominent treatment-associated side effects, which could be easily identified by patients, these trials could be considered as single blind rather than double-blind" Therefore it is likely that treated patients dropped out (like that youtube video I posted before) because of the unpleasant nature of injecting interferons. Furthermore, it would be extreme if the authors mean "progressed" in terms of actual disability progression, because only 10% of relapses result in permanent disability (sorry, no source!) - the assumption really is a worse-case scenario, and not quite realistic. However, I have to agree that trial withdrawals are generally deemed to be failures (although say in cancer, they are not considered "dead" for example!), and the p-value of 0.50 really is awful.
I dont know what to say further, except to propose that the table be modified, perhaps even with a version of Laetoli's warning - would that work, etc?.io_editor (talk) 20:16, 19 April 2008 (UTC)
I would rather avoid warnings... It seems that we are a bit closer of reaching an agreement. Lets see how to do that improvement. Worst case scenario is a common way of showing that effects are strong (Even if being placed in the worst posible scenario there is an effect that effect most probably does exist). Would it be a solution to say that interferons have not proven delay of dissability progression?--Garrondo (talk) 08:48, 20 April 2008 (UTC)
It would be incorrect to say that. See where I am going to respond to slp1 below.io_editor (talk) 15:25, 20 April 2008 (UTC)
Excuse me—in the English Wikipedia, in-article warnings are unacceptable. Sorry. Fvasconcellos (t·c) 14:11, 20 April 2008 (UTC)
I accept that this works fine within WP. Nevertheless, just as Laetoli argued, the effect of an authoritive-looking WikiMed page can be that advice is TAKEN, even iuf not GIVEN. Patients google for theie particular interest - they would be a long time here before they would even find that disclaimer page. Just pointing it out.io_editor (talk) 15:25, 20 April 2008 (UTC)
I am afraid I am still against the table. Io io, your main argument has been to argue that meta-analysis and systematic reviews should not be used for various reasons and that we should therefore ignore the reliable sources guidelines and no original synthesis. I would also point you to WP:MEDRS which provides specific RS guidelines about use of reliable sources in medical topics, which also advocates the use of secondary sources and warns against using primary sources to debunk secondary sources as you seem to be trying to do. We just can't ignore guidelines and policies, no matter how much you want it, no matter how many 'warnings' you want to add to it. This is not the place to change the policy and guidelines: go to the talkpage of those pages and try to get consensus to change them there. Slp1 (talk) 13:13, 20 April 2008 (UTC)
Please excuse me Slp1, I wrote too much last time. The Cochrane reviews are well-respected, but you have to read what it really says - here.
  • Objecting to the rules of the older trials (which allowed drop-outs, etc) relative to newer standards, the authors makes an extreme assumption "If interferon-treated patients who dropped out were deemed to have progressed (worst case scenario) the significance of these effects was lost."
  • In reality, interferons are nasty, and some percentage of patients quit due to side effects.
  • Even if all of these patients had an MS relapse, only around 10% would suffer permanent progression from that particular relapse (of course, more relapses could be possible, but not to all patients).
  • The actual result of the meta-analysis is in the Conclusion: "The efficacy of interferon on exacerbations and disease progression in patients with relapsing remitting MS was modest after one and two years of treatment."
  • The authors' final statement does accept the efficacy, the only reservation is that the efficacy is modest. What is in the table is very much the same (take a look again).io_editor (talk) 15:25, 20 April 2008 (UTC)
We are going round and round, io io, I fear. We cannot use the table because it is original research and synthesis. It doesn't matter if you think the Cochrane review is weak or problematic, because WP prefers the metaananalyses/systematic reviews of named, recognized researchers in the field, rather than the research, opinions and criticism of anonymous WP editors, however right they may be. "The threshold for inclusion is verifiability, not truth"WP:V If you have opinions/criticisms/improvements on the Cochrane reviews or any other reviews, write a paper and have it in published in a peer reviewed journal. Yes, the conclusions of the Cochrane review can be included in the article. No, the table, cannot be, for policy reasons. And I do not agree that it is "very much the same": I think it is misleading OR, as I explained above). Slp1 (talk) 18:53, 20 April 2008 (UTC)
I dont see any OR in the table - these are the results. What do you mean by telling me to go "write a paper"? What User:Laetoli started with was the statement that "...claiming that any of these treatments limit disease progression especially in view of more recent meta-studies that dispute such claims, particularly in the case of the interferons (see Cochrane reviews)." In fact the Conclusion of the Cochrane review literally supports the claims, modest though they may be, in black-and-white.io_editor (talk) 19:36, 20 April 2008 (UTC)
You may not see any OR in the table and similar comparisons, but other experienced editors do, and have explained why these comparisons are inappropriate synthesis on this page e.g. [7], [8] and on other pages, [9]. Please don't be an editor that doesn't get the point, and even if you don't yet understand WP policies well enough to see what the problem is, realize that you do not have consensus, and that as far as I can see you are the only editor who wishes the table reinserted. What I meant by go and write a paper is that we will only know if your original ideas/comparisons have merit if/when you get them published in a peer reviewed journal. When you do, we will know that they have reached appropriate scholarship standards and can include them. Until then, the table synthesises together studies that you (an anonymous editor) consider equivalent and compares outcomes that you consider appropriate, and that makes it impossible to include unless it has been published in this form in a peer-reviewed journal.


You can dispute with Laetoli the ins and outs of what the Cochrane review actually says. The text in the article should follow the conclusions closely, and I agree that there is modest evidence of improvement in the short-term at least. But that does not in any way validate the table, which is a totally separate issue. --Slp1 (talk) 20:09, 20 April 2008 (UTC)
Ok, so you refer to [10] where the writer based his argument that the table was "pieced together from multiple sources" - but so is EVERY wiki page. In your edit you gave an example where the results of a trial were not statistically significant - yet on this Table the distinction is clearly made between what was proven and not proven. As to the other page I dont see how that has anything to do with the table as it disputes something entirely different (safety). As to your claim that the table "synthesises together studies" and "compares outcomes", there is no "synthesis" as tehse were all placebo-controlled trials in treatment-naive, relapse-remitting MS, all designed to FDA standards (yes, with minor changes due to dropouts etc over the years) and while comparisons (by the reader, as NONE are stated in the table) are inevitable, they are in fact not mis-leading and I would go back to my earlier statement that Efficacy is the primary concern of MS patients.io_editor (talk) 20:42, 20 April 2008 (UTC)
OK, I will wait to see what Laetoli has to say about the Cochrane Review conclusion. Initially I read it too quickly - perhaps he did too.io_editor (talk) 20:42, 20 April 2008 (UTC)
I am going to give it one last try. The table is pieced together from multiple sources in which totally separate studies, determined to be comparable by you, are compared to each other using certain criteria chosen by you. There is no evidence (except your say-so) that the patient groups in the studies or that outcome measures are equivalent. There is no evidence that the differences in mean outcome rates are a statistically significant or represent any actual difference. There is no evidence that the table provides any meaningful information about comparative treatment efficacy, because it doesn't come from a reliable source. It leads people to come to a conclusion (as you admit yourself). Read this carefully, which is what 'synthesis' actually is:

Material can often be put together in a way that constitutes original research even if its individual elements have been published by reliable sources. Synthesizing material occurs when an editor tries to demonstrate the validity of his or her own conclusions by citing sources that when put together serve to advance the editor's position. If the sources cited do not explicitly reach the same conclusion, or if the sources cited are not directly related to the subject of the article, then the editor is engaged in original research.

Based on your other edits on this and other pages, you seem to have some sort of soft spot for natalizumab. Your table synthesises reliable sources together and ends up making natalizumab look like the best possible treatment. This is synthesis pure and simple and is not allowed. You need to find a peer-reviewed study that explicitly compares these different drugs. The issue seems to be a problem in understanding the difference between academic writing, and writing for an encyclopedia. This is not an academic paper where we are encouraged to be creative and do these kinds of innovative things and comparisons. This is Wikipedia, a very boring place where we only report, in summary form, what others have written and directly compared. Sometimes learning to understand the difference between academic writing and encyclopedia writing is a challenge, I realize. But these drugs have not been compared by reliable sources in the way you have tried compare them. And if they haven't made the comparisons, neither can we. Slp1 (talk) 21:25, 20 April 2008 (UTC)
  • re - Natalizumab. I did not think, with the earlier focus on the Cochrane reviews, that this is where it was going to end up. But I see the WP definition of synthesis, and yes to be brief, then it is indeed a sort of synthesis. But is it “advancing the editor’s position”? or just showing glaringly obvious differences? - well, that can be construed as you please, and no editor can defend against that. But I will come back to biggest of these "differences" in a moment.
  • But I see also that MEDRS lists NEJM first, and I am reminded of this, where N is described as “by several criteria, is an advance over current therapies” in the MS field. Perhaps WP is such “a boring place” that such medical advances should not see the light of day, even in “the summary form” that you refer to. After all, since biblical times, fighting disability successfuly has been a sort of mirage, never reachable. This anonymous editor certainly admit to find N exciting, all the papers & anecdotes I read, I gave links previously here. I wonder, at least within MS and CD, what is there NOT to have "a sort of soft spot for Natalizumab"? I have, I admit it, its a big medical advance and yet it is constantly castigated as a killer by the media. A sort of Galileo.
  • As to your statistical issues, what objection do you have to stating that some drugs have, and some drugs have not, proven to limit disability progression? These are unambiguous facts. That was the original issue, and is the real "MS" issue. As for comparator studies, there is a box at the bottom for notes, and that could be said, if it would please you. beyond that, I would be interested in seeing what Laetoli has to say, if he can find his way in this circular discussion - which I now doubt greatly.io_editor (talk) 03:24, 21 April 2008 (UTC)
I have answered in part on your talkpage, but will deal with the content issues here.
  • Based on the above it seems we are agreed that the table is original synthesis. As such it cannot be included either in the body or in the footnotes.
  • If there are published 'comparator' studies, suggest them and they can probably be included. But we ourselves cannot compare individual study results, for all the reasons I have listed above. I have stated the reasons why we cannot compare the drugs (including their effectiveness on disability progression) many, many times and ask you to consult the above section for details. Slp1 (talk) 12:54, 21 April 2008 (UTC)
The NEJM article and the others in the same issue are a good ones: they are relatively recent, and as you say, Ropper says that N is an advance over current therapies, which incidentally a view is currently reflected in the WP article which says "Comparisons between immunomodulators (all but mitoxantrone) show that the most effective is natalizumab in terms of relapse rate reduction". Note that Ropper also says that "It is tempting to project these [abatements in clinical progression] over a patient's lifetime, but there are no data yet to support such a view." Slp1 (talk) 19:14, 21 April 2008 (UTC)
Just a note to say that, once a therapy in any serious disease is a good one, that's the end of placebo-controlled trials for that drug, on ethical grounds...io_editor (talk) 02:05, 22 April 2008 (UTC)

I agree with Slp1 - we can only report findings and try to interpret them accurately taking into account conflicting views between professionals working in the field. This also involves clearly distinguishing between measures of 'disease severity' during a relapse and 'abatements in clinical progression over a patient's lifetime'. It is easy for the patient to confuse the two and as Ropper has explained, none of the DMDs have been shown to achieve the latter. Laetoli (talk) 13:37, 24 April 2008 (UTC)

I have read the Ropper article and the full sentence mentioned says the following: A further compelling result was the abatement of clinical progression (17 percent of patients receiving natalizumab had progression vs. 29 percent of those receiving placebo) and a similar prolongation of the interval before neurologic deterioration. It is tempting to project these improvements over a patient's lifetime, but there are no data yet to support such a view. As I understand it there has been a decrease in disease progression, and it is said verbatim in the reference, even if it is only during the years of the study. Of course longer longitudinal studies are needed to see if this decrease mantains over time or after some time MS patients on Natalizumab recatch patients on the other treatments groups. Would be a solution to say something as "preliminary data points to a effect in disease progression, but studies on the long-term effects are needed."--Garrondo (talk) 07:46, 25 April 2008 (UTC)