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Don't be too promotional[edit]

The paper in the NEJM, written by Novartis, was understandably enthusiastic. But other doctors whose job is to point out flaws and limitations in clinical trials have done their job. For example, Richard Lehman at BMJ:

Richard Lehman’s journal review—8 September 2014

This is the JAMA article Lehman refers to. Recognizing Worsening Chronic Heart Failure as an Entity and an End Point in Clinical Trials The point is that hospitalization isn't a valid end point, because the criteria for hospital admission are so arbitrary.

Attempts have been made to change the terminology from acute heart failure to hospitalized heart failure. However, hospitalization is a disposition and not a clinical diagnosis. There are no established criteria for admission or discharge for patients with heart failure, and, unlike myocardial infarction, there are no specific diagnostic criteria or pathophysiology unique to patients hospitalized for heart failure....

--Nbauman (talk) 09:01, 15 September 2014 (UTC)

Edits of September 14-15[edit]

@Nbauman: I just wanted to touch base with you regarding the recent edits on this article, with which I have some concerns. While not a cardiologist (perhaps you are?) my impression is that the expert commentary on this trial has been mostly positive. For example:

  • The Jessup editorial, which is summarized here but not give the benefit of the extensive quotes given to critics
  • Sanjay Kaul had very positive remarks here
  • Clyde Yancy, chief of cardiology at Northwestern made positive commments here
  • More positive comments from Milton Pacer5 of UT Southwestern here
  • Favorable comments on the American Heart Association Blog here

I also certainly understand that there is some skepticism in some corners about the trial design and endpoints, and that this will likely continue to be true for the forseeable future. It would be good if the article could present this in balance way, without overemphasizing either the optimism or the skepticism.

Another point of concern I had was the somewhat inflammatory direct quotes being used in the article, which I don't feel are ideal compared to the use of summaries that put less emphasis on the most extreme viewpoints expressed by partisans in the discussion. I realize that these are real experts, and they are reliable sources. But just because they made an extreme remark doesn't mean that including it in the article adds value.

thanks Formerly 98 (talk) 23:58, 15 September 2014 (UTC)

Thanks for the heads up, Formerly 98, but this is unacceptable. You're blanking out all the criticism. It has to go back.
The purpose of a Wikipedia article, in my mind, is not to tell readers that a new drug is good and they should ask their doctors about it. The purpose is to help patients, and anybody interested in medicine, to understand how medical science works, and how medical research works. These conflicting ideas illustrate how that process works, by showing the important features that a clinical trial should have, and how PARADIGM-HF missed some of them, in the opinion of Lehman and other expert critics.
You're reading different sources than I am.
Lehman is a major expert on clinical trials who has served on many guidelines and review committees. This is a point-by-point analysis of the problems with the trial.
The BMJ is a major medical journal, one of the "big 4" along with the NEJM, Lancet and JAMA. You can't give Forbes and PBS equal weight with BMJ. And you can't just count sources pro or con with a Google search. You have to look at the specific issues they raise.
Even the NYT quoted a critic of the study.
Milton Pacer is a fine cardiologist (I've heard him on panels) but he's the second author on the paper, and like everybody else in the PARADIGM-HF trial he was taking money from Novartis. He wants to get paid for his work. Fine. I would too. He's a (paid) advocate for LCZ696. He honestly believes in it. Fine. What else do you expect him to say?
I know people from Novartis and from their public relations firms. I like them personally. They're very good at generating news stories, which is their job, and there's nothing wrong with that. What is wrong is to avoid asking what the other people, without PR budgets, are saying.
I appreciate Novartis' research and development. I hope LCZ696 is a life-saving drug and they make a billion dollars. But we can't tell yet after a study like this until the weaknesses that Lehman pointed out are resolved.
Gary Schwitzer is a published expert and academic who studies health news and its bias. He wrote an evaluation of the coverage of LCZ696 on his blog. Schwitzer gave many sources that are "critical" of the trial.
Actually it's may not be meaningful to divide the comments into "critics" or "favorable" or "unfavorable." When someone publishes a study, the job of the scientific community is to pick it apart and see what the strengths and weaknesses are. Every scientist is a critic in the sense that he reads the study critically and looks for flaws (which are inevitable). That's particularly important in this study that was (apparently) entirely controlled by Novartis.
The words that the critics use are the words that they, as medical experts, use to express their ideas. They know what they're saying. You can't tell them, "That's too inflammatory, you can't say that." If they are inflammatory, they know what they're doing. You're not a medical expert. You can't change their words to soften their points or to make them "nice." That violates WP guidelines, such as WP:CENSOR and WP:NPOV. WP:NPOV isn't the median view, it's the best arguments on both sides. Lehman and the BMJ are not "extreme." They are holding medical investigators up to a strict standard of evidence. Do you want your doctor to prescribe a drug for you based on a weak standard of evidence? Based on a PBS story?
If you read the journals, like BMJ, Lancet, JAMA, NEJM, and Annals of Internal Medicine, you'll see that there was a big debate, which is now mostly over, about whether drug companies have sufficiently disclosed their trial results. According to a huge number of WP:RSs, this is a major problem. There were some companies, like Medtronic, that were committing scientific fraud. The drug companies are actually conceding this point. But the degree of control that Novartis had over this study is unusual by today's standards (according to Lehman) and belongs in the entry.
The burden is on you. In order to delete this, you have to reach a consensus that it goes out. You haven't done so. --Nbauman (talk) 01:35, 16 September 2014 (UTC)
Hi Nbauman,
I'm not sure I agree that the burden of proof is on me, but let's try to reach consensus before getting into a discussion about what happens if we fail to do so.
  • First, I notice that you expanded the section on the Jessup editorial after/while I undid the addition of a lengthy criticism by Lehman. This offsets some of my concern and I agree that expansion of the critical material is now possible without drifting into WP:NPOV
  • With respect to your comment "WP:NPOV isn't the median view, it's the best arguments on both sides." I disagree. Per WP:NPOV:
"Neutrality requires that each article or other page in the mainspace fairly represents all significant viewpoints that have been published by reliable sources, in proportion to the prominence of each viewpoint in the published, reliable sources."
  • I'm a little unclear on your comment about "The drug companies are conceding that they committed research fraud". I'm sure that there are specific examples of this, just as the Retraction Watch website daily lists dozens of new examples of fraudulent research by academic investigators. But we do not overgeneralize and raise the red flag of possible research fraud in every article describing a remarkable result obtained by academic investigators, we merely note that the significance of the result cannot be judged until other scientists have had time to evaluate and reproduce the data. In this case, even if the AllTrials effort fails, the data and trial design will be evaluated by FDA and EMA.
  • Which guideline and review committees has Lehman served on such that establish his credibility as a notable expert? A quick search of pubmed and BMJ shows that he is not a cardiologist, that the vast majority of his 35 or so publications are opinion pieces and not peer reviewed literature, and that he was senior author on only a handful of these. He doesn't write for BMJ, which is peer reviewed, he writes for the BMJ blog which is a different situation I think.
  • With respect to censorship, I agree with you, but I think we have to exercise some editorial judgement. It would clearly be inappropriate to include quotes such as Sanjay Kaul's remark "At long last, a winner!" or Clyde Yancy's remark "They are not just positive, they are remarkably positive and positive in every dimension." Likewise, I think the remark about "the worst of all possible trial designs" is just a non-specific broadside that adds little to the article. Our goal is not to find and include the most polarizing quotes we can lay hands on, and in the case of Lehman we are reaching outside the cardiology community to obtain them.
  • As soon as I finish this note I will re-add some of the deleted material as a possible compromise. Let me know what you think.
  • I very much appreciate your thoughtful and respectful presentation of your side of this argument, and wish all editors expressed themselves as diplomatically and as clearly.
Formerly 98 (talk) 12:58, 16 September 2014 (UTC)

I've done a BOLD rewrite with proposed compromise language, trying to keep the number of direct quotes (which tend to add impact and credibility) similar on both sides of the issue. It currently has about 3:2 more text on the criticism side than on the proponent side, but my impression is that the opinions found in the literature are leaning about 3:2 in the other direction. I think the article needs a little more material on the pro side, but can accept the present version as it is if you will do so.
Please note that as (what I regard as) a concession intended to reach quick agreement, I've kept Lehman's rather inflammatory "worst clincial trial design" comment, but have not included any of the many very laudatory remarks from the proponent side calling this "new hope for patients", a "paradigm shift" and the like. To be honest, I really don't want to spend a whole lot of time on this, as high quality secondary sources including peer reviewed review articles will be out within a few months, and we'll have to revisit the article at that time.
Let me know what you think. Formerly 98 (talk) 15:37, 16 September 2014 (UTC)
This rewrite doesn't say the same thing. There are 3 problems here:
(1) This is more POV. For example, the NYT itself didn't say that Bove was "critical," that's your interpretation. I prefer to let people speak in their own words, and let their words speak for themselves as much as possible.
(2) You didn't cover all the criticisms, and you didn't explain the criticisms in enough detail for the reader to understand the points they're making.
For example, Lehman and others said that the dosage of enalapril was sub-therapeutic. That's an important point. The BMJ has said that one way to bias trials is to use a sub-therapeutic dose of your competitor's drug. Think about that. You simply paraphrased him as saying, "the trial results were likely biased by the use of inappropriate doses of enalapril and valsartan." How could a non-specialist read that and understand what the issue was?
Lehrman wrote that we can't distinguish the effect of the sacubitril from the effect of the valsartan, and Novartis should have had a trial of valsartan with and without sacubitril. Think about that. How do we know that sacubitril has any benefit at all? We don't. You deleted that completely.
You wrote, "the patient population was not typical of those seen in clinical practice." What Lehman and others wrote was that his heart failure patients, and most heart failure patients, are elderly, but these patients were young, median age 64. The journals repeatedly say that you can't apply clinical trials in one population to a different population. Your summary misses this important point.
Everything in that quote from Kaul is meaningless. Any drug could be "potentially" used. But if the study demonstrates effectiveness in a young population, how can you recommend it in an elderly population? Of course the data require an FDA review; every drug does. In WP terms, this violates WP:PEACOCK, WP:CLICHE. It also violates Gary Schwitzer's rules for good medical writing
I wrote a summary of Jessup's editorial in NEJM, to include all the positive arguments for PARADIGM-HF to balance Lehman's criticism. Why did you take it out? Why do you replace a WP:MEDRS like the NEJM with sources like Forbes? Jessup also describes the mechanism. Why do you replace her discussion with an article in German?
(3) It's more disorganized now and harder to read. It's organized by quotes rather than ideas. The structure I tried to use was to sumarize the NEJM article, the NEJM editorial, and the Lehman review for balance, with a few other comments that added something or said it more clearly, that our readers could look up, like the NYT story. It seems like you didn't recognize that structure. Now it's chopped up, without any logical order that I can see. You no longer have the same ideas together, like patient population and mortality.
For example, you discuss the patient patient population problem in 2 different places, quoting Mann and quoting Lehman. How is a reader supposed to follow this?
You discuss the mortality in 2 different places. You give the 17.0% and 19.8% death rates in one place, and then give the 3 percentage points, which puts it in perspective, 4 paragraphs down.
You discuss the dosage in 2 different places.
Lehman is first an academic doctor who serves on committees, second a practicing GP who treats patients with heart failure, and third an excellent writer, which is why BMJ gave him a weekly column which is highly regarded and popular among doctors. You and I will never understand the medicine as well as he does, or write it as well as he does.
That's why I paraphrased him at such length about his take on the PARADIGM-HF trial. He can write it better than I can, and the best I could do was follow him. This is the best summary of the informed criticism of the study that you will ever find. You can't improve it by breaking it up or shortening it and adding other sources (like Forbes). Everything you've taken out was imortant.
I don't know about you, but I live in the U.S., and we are forced, whether we like it or not, to be medical consumers. (And according to the BMJ, their neocons are pushing the U.K. in the same direction.) People come to Wikipedia to understand medicine. I'm trying to help them by explaining it. You don't do that by mindlessly quoting the abstracts that were written by drug companies (notice the abstract doesn't mention the age of the patients), or by quoting doctors who are giving reporters platitudes, or by quoting Forbes and PBS.
You do that by putting the story in context. For example, explaining the science behind the study, which you do by explaining its strengths and weaknesses, which is what Lehman does every week. I'm not doing WP:OR; I'm getting my ideas from the peer-reviewed medical literature. For example, the BMJ has long said that one of the tricks that drug companies use to bias their studies is to use a sub-therapeutic dose of their competitor's drug. For example, if you do a RCT, you compare one drug to placebo. How can you know in this study whether the reduction in mortality is due to the sacubitril or the valsartan? Really, think about that. I'm trying to teach people how to think.
Ragnar Levy wrote in JAMA that medical writers have an ethical responsibility to make sure that their writing is accurate and that the people who read it understand it -- because people make important decisions based on medical writing. I've seen people like Medtronics say things like, well, this treatment is useless and dangerous, but we can't say that, so let's compromise and say, "Caution should be used." For that reason, I'm not willing to compromise on fundamental issues. And explaining exactly what's wrong -- and right -- with the PARADIGM-HF trial is a fundamental issue. This rewrite doesn't do that.
And if you do add new sources, I wish you would include the full citations in WP style, with title, author, publication, date, and url. A citation like "PARADIGM-HF: New Drug Class Outclasses ACE-I in Chronic HF" isn't too useful.--Nbauman (talk) 18:44, 16 September 2014 (UTC)

I'll just throw out a few comments and responses.
  • "I prefer to let people speak in their own words, and let their words speak for themselves as much as possible."
According to WP:IMPARTIAL, The tone of Wikipedia articles should be impartial, neither endorsing nor rejecting a particular point of view. Try not to quote directly from participants engaged in a heated dispute; instead, summarize and present the arguments in an impartial tone.
  • "You didn't cover all the criticisms, and you didn't explain the criticisms in enough detail for the reader to understand the points they're making"
True. But we have included the arguments of those who viewed the trial results very favorably to an even lesser extent, and in any case the purpose of a encyclopedia is to summarize. Per WP:UNDUE, Undue weight can be given in several ways, including, but not limited to, depth of detail..
  • "I wrote a summary of Jessup's editorial in NEJM, to include all the positive arguments for PARADIGM-HF to balance Lehman's criticism. Why did you take it out? Why do you replace a WP:MEDRS like the NEJM with sources like Forbes? Jessup also describes the mechanism."
I agree this may not have been ideal. I was trying to keep a balance among viewpoints according to their prominence. I felt that the extensive use of quotes for Lehman's criticisms, and the almost desultory listing of statements from Jessup's editorial created imbalance, but was not able to effectively edit that section because while I have access to Jessup quotes in other publications, I don't have access to NEJM.
  • "Everything in that quote from Kaul is meaningless."
Not at all. You want to quote extensively from a primary care physician who attacks the statistical validity of the trial. One of the best known cardiologist in the country called it "statistically persuasive". Its not only meaningful, it addresses the exact point that you are trying to address with your Lehman quotes.
  • "It's more disorganized now and harder to read." - Yes, I suppose you are correct.
  • "Lehman is first an academic doctor who serves on committees, second a practicing GP who treats patients with heart failure, and third an excellent writer, which is why BMJ gave him a weekly column which is highly regarded and popular among doctors." We don't need to argue about this for the moment as I am not contesting your use of his blog in the article. It may need to be replaced later as higher quality, WP:MEDRS sources become available, as it is not peer reviewed.
  • "People come to Wikipedia to understand medicine. I'm trying to help them by explaining it. You don't do that by mindlessly quoting the abstracts that were written by drug companies" Yes, but please remember that you have to stay within the bounds of WP:NPOV
Wikipedia aims to describe disputes, but not engage in them. Editors, while naturally having their own points of view, should strive in good faith to provide complete information, and not to promote one particular point of view over another., and WP:ADVOCACY
Wikipedia is not a venue to Right Great Wrongs, to promote ideas or beliefs which have been ignored or marginalized
And the determination of what sources are and are not reliable is determined by WP:MEDRS. From my POV, we should not be using any of these references, but should instead leave this article as a stub until WP:MEDRS compliant sources (secondary and teriary peer reviewed articles) become available. When this happens, by the consensus of the Medical Editors of Wikipedia as a whole, those from pharma authors will be just as admissible as those from pharma critics, academics or whoever. If you want to change that you need to take it up at the Medicine Project Talk page.
  • "For that reason, I'm not willing to compromise on fundamental issues." If don't believe you really feel this way, as you have been very willing to work toward consensus so far. If you really do, you should write a blog, because consensus is one of the three pillars of Wikipedia, and consensus is not reached without compromise.
Why don't you take a stab at this and try to improve what I wrote (or revert it and start over). But please take my comments above into account. It is unlikely that I will revert or substantially edit anything you do provided that you make some effort to address my concerns. But I reserve the right to revisit this question in a few months when WP;MEDRS compliant sources become more available.
Sorry we disagree so strongly, but I appreciate your good faith efforts to discuss the issues. Thanks Formerly 98 (talk) 21:38, 16 September 2014 (UTC)
Well, you can't write about a study in a medical journal without reading the papers in the journal. Send me an email and I'll send you the PDFs. --Nbauman (talk) 07:26, 17 September 2014 (UTC)

I was interested in Lehman and your comments on the dosing in this trial, and thought I would bounce what I found off you and get your impressions. This is all WP:OR of course, but that is allowed to some extent on Talk pages, and its really just for discussion purposes.

  • The Valsartan Heart Failure Trial used a target dose of 320 mg per day. This dose was achieved by 84% of subjects, for an average daily dose of 254 mg. Mortality reduction was only seen in the small subset of patients who were not on ACE inhibitors at baseline. Because this number is small, the trial does not really provide an accurate value for the hazard ratio. No compliance data is in the paper. The label recommends 320 mg daily.
  • An analogous trial for enalapril used a target dose of 20 mg per day. The achieved average daily prescribed dose was 16.6 mg per day, with just shy of 50% reaching the target dose of 20 mg per day. Interestingly, the paper notes that 32% of the enalapril group and 42% of the placebo group stopped taking their medication by the end of the 48 month study. In spite of the small fraction of patients reaching the target dose and the low compliance (would be nice to have this data for valsartan!), the relative risk of death relative to placebo was reduced by 16%, and the relative risk of CV death by 22%.
  • A second trial examined the effect of enalapril dose on survival. The trial randomized patients to two groups. Patients in both arms were titrated to the maximum tolerated dose, with a cap of 20 mg per day in the low dose arm and a cap of 60 mg in the high dose arm. The mean dose achieved in practice was 18 mg per day in the low dose arm and 42 mg per day in the high dose arm. After 12 months 18% in each arm had died (p = .99). The authors state that the trial was 80% powered to detect a 13% reduction in mortality. Changes in hemodynamic and other biomarkers was similar between the two groups.
  • The CONSENSUS trial of enalapril in severe heart failure attempted to titrate patients to 40 mg per day. The average daily dose at the end of the trial was 18 mg and about half of patients achieved the target dose. (Remember that because of the 40 mg cap, the mean is not going to be equal to the median dose). The reduction in mortality relative to placebo was 40%, but I would probably steer clear of cross trial comparisons as this is a very different patient population.

So looking this over for about an hour (perhaps you have spent more time than I), there seems to be good evidence that doses above 20 mg will be tolerated by many patients, but also some evidence that such higher doses will not further decrease mortality. I can certainly see room for disagreement on this point, but I think it is a little more complicated than Lehman's dismissal of the 20 mg dose as "sub-therapeutic". My opinion is that if the trial had attempted to titrate enalapril to higher doses, only about half of patients would have achieved them. With only half of the enalapril patients achieving the higher dose, the impact on survival of a 40 mg dose would have to be more than twice that of the 20 mg dose in order to change the conclusion that LCQ696 had a survival benefit. Such a large impact of the larger dose seems pretty much ruled out by the data above.

It will be interesting to see how the discussion develops. They will eventually have to defend their decision to the FDA, the EMA, and the cardiology community.

A couple of other points on which I disagree with Lehman:

  • Lehman suggests that the use of over 1000 clinical trial sites was simply a ruse to "gain influence". In fact, recruiting over 8000 patients for a multi-year trial is no mean feat. Even with these 1047 trial sites, the trial took over 4 years to enroll. Would Lehman be happier if the trial used half as many sites, and took 8 years to enroll?
  • Lehman ridicules the claimed efficacy as leading to a NNT of 35 to prevent death over 2.5 years. This would be a great analysis (though I would happily take a drug with an NNT of 35 for preventing my death over the next 3 years) if this was a disease like flu, for which the risk disappears at the end of the trial. But it doesn't. Almost all of these patients will die over 10 years, and almost all will die of heart failure. If you look at the survival graph in the paper, the lines are diverging almost linearly from Day 1. The percent difference was smaller at 1 year, and will be larger at 5. Extrapolating (which I know is risky), I get an estimate of about an extra year of life for LCZ696, and its difficult to look at the data and conclude that it would be less than 6 months. Its less than it could be, but at $2500 per year, translates to less than $40K per QALY. Even the NHS will pay for that.

Again, all this is just WP:OR, and for purposes of discussion only, as I am interested to hear your opinion. Formerly 98 (talk) 14:26, 17 September 2014 (UTC)

edits today[edit]

I reordered this article per WP:MEDMOS. I removed projections about potential price per WP:CRYSTALBALL. I reduced the weight given to the WP:PRIMARY NEJM study which was WP:UNDUE and was driven by WP:RECENTISM. I added information about the the 2010 clinical trial on hypertension, based on the most recent review article. Jytdog (talk) 02:57, 18 September 2014 (UTC)

WP:RECENTISM is not a WP guideline, it's a personal essay. What are you waiting for? It already has lots of comment, in the lay press and medical publications.
As written, this entry is inaccurate. Valsartan/sacubitril isn't in clinical trials; a major RCT has been completed and published in the NEJM.
Why didn't you put the link to the NEJM study (which has the final results) under "Medical uses," where you have the other trials (which only have preliminary results)?
And why didn't you include the Jessup editorial, which is the most reliable secondary comment I can think of?
Under WP:WEIGHT, the weight accorded to a subject in the entry should be proportionate to its coverage in WP:RS. The coverage of this trial was enormous. It also raised a lot of important issues about how we should evaluate the treatment of heart failure. Shouldn't the weight be proportionate to its coverage?
Is it enough to say, in effect, "some people like it, and some people don't like it"? Shouldn't we give the reader an idea of why WP:RSs like it or don't like it? --Nbauman (talk) 22:29, 25 September 2014 (UTC)
Trying not to react to tone... responding to each element:
What are we waiting for? An actual review article to discuss this. WP is not a gossip rag and the ruckus is just that. MEDRS counsels not to fall to prey to WP:RECENTISM and indeed to wait for reviews to discuss the primary source.
You seem to be under the impression that this investigational drug is actually marketed and in medical use. It is not used medically (in other words, no doctor is prescribing it to any patient in actual clinical practice) anywhere in the world yet as far as I know. Please bring a source to correct me if I am wrong.
In the medical section, our article just says that LCZ696 is in clinical trials. That content is supported by two review articles that discuss LCZ696 as a clinical candidate in the indications mentioned. The content relies on secondary sources - what we rely on everywhere in WP as we should.
Jessup is not a secondary source as we define them in MEDRS.
(combining last two points) There was a truly absurd amount of weight given in this article to the tizzy over the PARADIGM clinical trial. There was a lot of hot air blown over the interpretation and "meaning" of the PARADIGM trial. All that hot air has pretty much already been spent. Blip, gone. Recentism. Real world is - there is no drug on the market yet (and there may never be one - it could fail to get approved) and if LCZ696 does get on the market, we will not know for a long time whether or not LCZ696 has "transformed" care of heart failure (or hypertension) or turns out to be an incremental improvement or turns out to have some nasty side effect and gets withdrawn from the market. We are an encyclopedia not a newspaper or gossip rag or crystal ball. In health related articles, we want to give reliable information about health. I don't see anything (and you provided no source) showing that anything about the tizzy matters from any long term perspective. (there has indeed been lots of speculation by the talking heads about what might happen or might matter - which is all the hot air/navel gazing I mentioned).
So that's my perspective - I tried to answer all your questions. Am very open to hearing other reasoned perspectives! Jytdog (talk) 23:00, 25 September 2014 (UTC)
I also want to note that if you look at the overall article right now, the PARADIGM trial already has the longest section -- the most weight. I think that the level of detail is inappropriate and would cut it down lots more if i were the only one working here, but I left it much longer than I would like on purpose, as i doubted you and perhaps others would tolerate it shrinking more than this. But I cannot tolerate it expanding much more. I tried to strike a compromise so we could have stable content that we could have consensus for (not consensus that makes any of us delighted but something we can all live with). Jytdog (talk) 23:37, 25 September 2014 (UTC)
about "in clinical trials" - I just checked and there are indeed ongoing trials of LCZ696 in both heart failure and hypertension; so it is true that LCZ696 is in "clinical trials" per se. However in terms of having enduring content, there ~may~ come a time at some point before the drug is approved when there are no clinical trials running. So I changed "clinical trials" to "clinical development" which is the same "phase" of bringing a drug to market, but less specific and will cover that unlikely possibility. Jytdog (talk) 23:54, 25 September 2014 (UTC)
What definition are you using of a "secondary source"? --Nbauman (talk) 00:27, 26 September 2014 (UTC)
Wikipedia:Identifying_reliable_sources_(medicine)#Definitions Jytdog (talk) 00:29, 26 September 2014 (UTC)
if you read through all of MEDRS carefully and sit back and reflect on it (especially in light of WP's mission and the very strong theme in our policies, WP:VERIFY and WP:OR, and the guideline WP:RS, that all content should be based on secondary sources) the thrust of MEDRS is that in the charged arena of health content, we go slow, we wait to write content until the scientific community has had time to reflect and put results of original research publications (primary sources) into perspective. There is a section in MEDRS on "Biomedical journals" that really brings this home: ""Peer-reviewed medical journals are a natural choice as a source for up-to-date medical information in Wikipedia articles. They contain a mixture of primary and secondary sources. Journal articles come in many types, including original research ranging from vast studies to individual case reports, reviews, editorials and op-ed pieces, advocacy pieces, speculation, book reviews, letters to the editor and other forms of commentary or correspondence, biographies, and eulogies. It is usually best to use reviews and meta-analyses where possible. Reviews in particular give a balanced and general perspective of a topic, and are usually easier to understand." The Jessup piece is called by the NEJM an "editorial" and that passage I just quoted makes it clear that editorials are not reviews.. and reviews are the high standard of sourcing that we should aim for... those, and statements by major medical and scientific bodies are the best, to realize WP's mission to give readers really reliable information that reflects scientific consensus and avoids WP:OR (and by "OR" I mean editors picking this or that original research publication or commentary and deciding on their own authority to give that WP:PRIMARY source a lot of weight - that decision is OR). There is so much hype and emotion around health, and we should steer clear of all that.... in my view. That's my understanding of the deeper issues, fwiw. Jytdog (talk) 00:39, 26 September 2014 (UTC)
I agree with you that a review article is the best source, and when I do a medical literature search, which I do 2 or 3 times a week, that's the first thing I look for. But if, for example, you read the NEJM Case Records, you'll see that they often deal with a condition for which there are no review articles or meta-analyses.
I agree with everything you've quoted. It says that review articles and meta-analyses in peer-reviewed medical journals are "usually best". Review articles and meta-analyses in peer-reviewed medical journals are one acceptable source. But I read that to mean that you can also use editorials in peer-reviewed journals if the best is not available.
Can you quote (or underline) the text which says that editorials in peer-reviewed journals are not WP:MEDMOS reliable sources? --Nbauman (talk) 14:17, 26 September 2014 (UTC)

──────────────────────────────────────────────────────────────────────────────────────────────────── Editorials are WP:PRIMARY. And of course blah blah blah blah blah primary sources can be used under RS and even under MEDRS be we should not use and we should use great secondary sources. I try to lift articles I work on to our highest standards. Why in the world do you want to use the crappiest kind of source allowed? Jytdog (talk) 16:21, 26 September 2014 (UTC)

The NEJM refers to features like Jessup's as "Editorials," but they are usually, as in this case, a commentary on a primary source. Your quote goes on to say:
A secondary source provides an author's own thinking based on primary sources, generally at least one step removed from an event. It contains an author's interpretation, analysis, or evaluation of the facts, evidence, concepts, and ideas taken from primary sources.
Jessup's editorial provides the author's own thinking based on primary sources, one step removed from the original research. It contains the author's interpretation, analysis and evaluation of the facts, evidence, concepts and ideas taken from primary sources. Therefore I conclude it is a secondary source as we define it in Wikipedia.
Why isn't it a secondary source according to that definition? --Nbauman (talk) 20:07, 26 September 2014 (UTC)
Please tell me - what is your goal - what do you want to actually do in our article? Jytdog (talk) 20:50, 26 September 2014 (UTC)
let me add that editorials are wierd animals. they are secondary-ish but they are not peer reviewed; i consider them primary because of that but it is quibbley/wikilawyer-y point -- the message of MEDRS is that we reach for reviews or statements by major medical or scientific bodies as much as possible. i never understand why people want to reach for lesser sources. anyway, enough of the theorizing - if all you want to do is add the source i wouldn't argue. if you want to add content based on it, that is a different discussion. so please do tell. Jytdog (talk) 21:33, 26 September 2014 (UTC)
Here's my goal. This drug is a notable drug. This publication is a notable event. It got a lot of coverage, much of which was in non-WP:RS publications, much of which was WP:PEACOCK, much of which was wrong, and much of which was overly promotional. The NEJM study, and abstract, were written by Novartis itself. It's a pre-approval advertisement for the drug.
I would like to write a WP entry, based on WP:RSs, which explain why the study was important, what the biological mechanism was, what the study concluded, and what comments other WP:RSs and WP:MEDRSs have made about the study. I want to put the manufacturer's claims and the critics' claims in perspective. I'd like to eliminate the WP:PEACOCK quotes like "new paradigm" and replace them with substantive arguments based on facts.
I think it should be written using the recommendations that Schwitzer gave for writing a medical news story. Schwitzer collected an enormous amount of useful information about the study. (Schwitzer is a published author, recognized expert, and academic, so his blog is probably a WP:RS. But even if you don't agree, these are guidelines that make sense.)
I'm not a doctor. If one doctor says that 20 mg/day is a reasonable dose of enalapril, and another doctor says that it's a low dose designed to make Novartis' drug look better, I can't decide who's right. I have read many articles in BMJ and NEJM which claimed that drug manufacturers regularly use a low dose of their competitor's drug to make their own drug look better. I think that an encyclopedia entry which repeats the NEJM article, which is Novartis' marketing claims, and doesn't also include the many critics who wrote in WP:RSs that the study has flaws, including a low dose of enalapril, is violating WP:NPOV and WP:ADVERTISEMENT. I believe that a WP article can't merely say, "some people argue that there are flaws in the trial," and give a link to the critics, without explaining in the article what those flaws are, clearly enough for an educated layman to understand what the problem is. I could censor any WP article by deleting the criticism, leaving the link, and saying, "some people criticise xyz." There are PR firms that get paid to do exactly that.
I once asked Gerard Piel, the editor of Scientific American, how he wrote an article. He told me that they weren't giving their readers a lot of facts. They were trying to get their readers to understand the methods of science: a scientist gets a theory, figures out an experiment to test that theory, performs the experiment, and sees whether his theory was right or wrong. I think that should apply to all science writing, including Wikipedia.
I think the important issue for our readers is not how many people died in each group, or whether some stock trader thinks the drug is a "new paradigm," but to help our reader figure out how a clinical trial is supposed to be done, why it's supposed to be done that way, and how the Novartis trial matched up against the requirements of a clinical trial. Lehman does that every week in the BMJ, and he did it for this trial. I don't know if he's right or wrong, but we should give both opinions so readers will know that these are the kind of debates that are going on. That's why I think it's important. And it can all be done within Wikipedia guidelines, if you simply follow WP:NPOV.
I used to write for a medical magazine, and our main subject was medical guidelines and review articles (not review articles, but reporting about review articles). When I first figured it out, I thought, this is great. All you have to do is make decisions based on gold-standard review articles, and medicine is simple. I then learned that for many or maybe most treatments, there are no review articles. If you start looking for things in Cochrane or PubMed, you'll find that out pretty fast. If we were to limit Wikipedia only to information published in review articles, we'd have a small subset of medical knowledge, most of which would be outdated, and it wouldn't be too useful. (And a lot of review articles, even in the NEJM, are written by people with financial stakes in one product, and their financial disclosures are now hidden behind a link.)
Since you asked. --Nbauman (talk) 23:48, 26 September 2014 (UTC)

──────────────────────────────────────────────────────────────────────────────────────────────────── thank you for that long answer. First, when you write "It's a pre-approval advertisement for the drug." I find that pretty disgusting and I would appreciate if you left that kind of POV WP:SOAPBOXing at the login page. It sounds like you want to turn WP into Schwitzer's blog. But WP is not Schwitzer's blog. Or into Lehman's column. But WP is not Lehman's column. Here, per WP:MEDRS we do not put a lot of stock in clinical trial results. Whatever the talking heads say as they go on and on and on and on, the glaring fact here is that LCZ696 is an investigational drug that is not approved for medical use anywhere in the world and may never be approved and the clinical trial and what various talking heads say about it, doesn't mean anything for clinical care. Based on what you wrote above, I removed all commentary about the trial and reduced the desciption of it yet further. Jytdog (talk) 00:00, 27 September 2014 (UTC)(edit my comments per strikeouts and underlines, with apologies for foolishly following suit Jytdog (talk) 00:32, 27 September 2014 (UTC))

following on.... this article is about an investigational drug. i wonder if it nbauman could satisfy himself by writing an article on the PARADIGM trial, and i wonder if there are enough MEDRS-compliant sources to enable a viable article such that it could survive a deletion review.. hm! There are a few articles focused on individual clinical trials in WP.... Jytdog (talk) 00:49, 27 September 2014 (UTC)
I wouldn't judge it that harshly Jytdog, he has a right to his opinion, and if he thinks anything written by pharmaceutical industry authors and pharma-associated authors is nothing more than propaganda, he has plenty of company. But I disagree with the comment "I want to put the manufacturer's claims and the critics' claims in perspective. I'd like to eliminate the WP:PEACOCK quotes like "new paradigm" and replace them with substantive arguments based on facts." which is the essence of WP:OR. We don't do that here. We gather and describe the opinion of experts as published in peer reviewed secondary sources. The opinions of Wikipedia editors aren't really what this is about. Formerly 98 (talk) 00:06, 27 September 2014 (UTC)
POV pushing doesn't belong anywhere in WP. Jytdog (talk) 00:08, 27 September 2014 (UTC)
Yes, but your expression of anger was directed on his stating his opinion on the Talk page and not in the article. As I understand it, he has the right to do that on the Talk page. Formerly 98 (talk) 00:11, 27 September 2014 (UTC)

──────────────────────────────────────────────────────────────────────────────────────────────────── first, i expressed disgust, not anger. second, nobody has any rights in WP. we all have privileges. which can be revoked. key part of WP:TPG that is wrong with what he said (and my reaction) that is relevant to this is WP:NOTFORUM. We talk about content and about sources and we ground that discussion on wikipedia policies, guidelines, essays, and the spirit of this project. Anybody's soapboxing on the issues at hand is out of bounds and unwelcome because all it does is lead other people (in this case, me) to do more of the same and soon we are in hell. would have been better had i simply said "Please leave your WP:SOAPBOX at the door" - in fact I will go change that now. which i did. Jytdog (talk) 00:32, 27 September 2014 (UTC)

Jytdog, I think you've crossed the line into personal attacks. I also think you don't understand what I'm saying. I've been to medical conferences where doctors who edited those those medical journals described how the editing process works. They said that articles that are controlled by the manufacturer are effectively advertisements, and shouldn't be published, and they've written that in their journals. I'm just repeating an increasing mainstream consensus of the medical community.
I see this in the major journals every week. Publishing a randomized controlled trial, where the drug company has control over the design and publication of the trial, gives just one side. They're written under the direction of the marketing department. Drug salesmen distribute them to doctors. Even the drug companies refer to them as marketing. Some doctors refer to them as advertising. That's not my opinion.
Journals usually get a commentary to give the other side (although they didn't give the other side in this case) Giving both sides is WP:NPOV. You're falsely accusing me of POV pushing and soapboxing. As I said above, I want to give both sides. You only want to give one side. You've even deleted all criticism. That clearly violates WP:NPOV.
I'm not going to get into an edit war with somebody who just summarily deletes anything he doesn't like, without even discussing it in talk first. It's a waste of my time to continue on this. I'm not coming back until there are some editors who understand medicine who can oversee this entry. --Nbauman (talk) 04:31, 27 September 2014 (UTC)
What I wrote was not about you; it was about the POV you expressed. And I struck it, and apologize for giving my opinion. And please stop stating yours; it doesn't belong here per WP:NOTFORUM. Will comment on your Talk page if you want to continue. Jytdog (talk) 12:23, 27 September 2014 (UTC)

single thing[edit]

The original phrase, "single molecule" was verbatim from the source cited. The intention there, as it was here, was to make it clear that LCZ696 is a single thing, not just a formulation of the two drugs together. Anypodetos changed that in this dif, with edit note "LCZ696 is not a single molecule". I understand the point, but the notion should be clear. I added content in this dif to explain that, so it now reads "LCZ696 is synthesized by co-crystallisation of valsartan and sacubitril, in a one-to-one ratio; it is not simply a formulation of the two drugs together." Happy to discuss. Jytdog (talk) 12:24, 18 September 2014 (UTC)

I also see your point, but I'm afraid the new phrasing is also wrong. "Synthesis" is basically the creation of new molecules. These two are synthesised seperately and then, as you wrote, co-crystallised. What about writing simply "LCZ696 is co-crystallised valsartan and sacubitril in a one-to-one ratio"? BTW, while this is interesting, it's probably of no pharmacological significance. As soon as the tablet dissolves, the two molecules float around independently in the gut, and they are also absorbed separately from each other. --ἀνυπόδητος (talk) 13:17, 18 September 2014 (UTC)
respectfully, what is your source for how LCZ696 is synthesized? The mongo source cites:
  • Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol 2010; 50: 401–414. PMID 19934029
for the statement :"The prototype of these drugs is LCZ696, a single molecule synthesized by co-crystallisation of a well-known angiotensin II antagonist, valsartan, and the neprilysin inhibitor prodrug AHU377 (1:1 molar ratio)". I looked at the Gu et al article, and it says "LCZ696 (trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2′′-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate) comprises molecular moieties of valsartan, a well-established ARB,11 and of the NEP inhibitor prodrug AHU377 ((2R, 4S)-5-biphenyl-4-yl-5-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester; Figure 1), which is metabolized to the active NEP inhibitor LBQ657 by enzymatic cleavage of its ethyl ester.12 LCZ696 is a novel single molecule in which the molecular moieties of valsartan and the molecular moieties of AHU377 are present in a 1:1 molar ratio. The details of the molecular structure of LCZ696 will be presented elsewhere (manuscript submitted)."
what is your source for how LCZ696 is synthesized? If your argument is semantic and not based on sources that describe how the molecule is actually made, please say so. That is an entirely different conversation. Jytdog (talk) 13:44, 18 September 2014 (UTC)
[1] shows (p.48) two structural formulae (valsartan and sacubitril) and a crystal structure that appears to be the two molecules plus sodium ions and something else built into a crystal -- but that's a bit small to decide. [2] also shows two molecules. I can find no source showing that and how the two are built into a single molecule (which, if true, would make the term "co-crystallisation" wrong). So, in a way, this is also a semantic issue: "co-crystallisation" and "single molecule" are mutually exclusive. Also, the chemical nomenclature you quote does not seem to name a single molecule. That makes one self-contradictory source (yours) and two that say they are two molecules (but none of them really reliable). It would be nice if we had access to the submitted manuscript you quote; but if you are right about the single molecule, the title, drugbox and header of our article are awfully wrong.
For your question about why I know how LCZ696 is synthesised: I don't, but it cant be both synthesised as a single molecule and co-crystallised. Sorry if I didn't make that clear. --ἀνυπόδητος (talk) 15:37, 18 September 2014 (UTC)
sorry but i don't agree. what the slide deck shows on slide 48, is a single molecule on the left (the same as figure 1 in the Gu et al paper) and its metabolites (the two separate drugs) on the right. It is a single molecule formed by co-crystalization - components in a cocrystal are held together by hydrogen bonds, etc and that is what the figure in Gu and in the slide deck are showing. this is not rocket science - we talk about macromolecules as single entities all the the time, even though they are made of subunits. We talk about "the" ribosome, about individual ion channels etc, even though they are made of subunits; they are stable, yet pretty easy to break apart. and as the slide deck says LCZ696 (the single thing) is "rapidly converted to NEPi and valsartan". btw I wrote to pubchem and asked them to correct the figure. they correctly provide a single molecular weight and formula for LCZ696. but the figure is wrong and shows the components of the drug in plasma after it is broken apart....Jytdog (talk) 16:10, 18 September 2014 (UTC)
My impression is as follows. The complicated crystal structure with the two molecules and the sodium ions basically show this "compound" as a complex salt. It is clearly a combination of two discrete molecules that are not covalently bound to each other and which dissociate from each other upon dissolution. But depending on how much one wants to stretch the definition of chemical terms, I suppose one could call this well defined mixture a chemical substance.
Two hypotheses for why they insist on calling it a single molecule. First, by establishing this one-to-one crystal form rather than mixing the two discrete powders in a pill, they help ensure that both dissolve and are absorbed at the same rate. They may be inordinately proud of this drug delivery strategy, of which I am aware of no prior examples. Alternatively, it may be some sort of patent strategy. By doing the HF trials with the co-crystal and the trials in some other indication with the two drugs as separate powders, they can price discriminate between HF and other indications, as the two forms would not be bioequivalent.
If the nature of this substance is confusing, I think it is probably a deliberate effort on the part of the manufacturer. As a chemist I object less to the price discrimination or whatever other goal motivates this behavior than I do to the bastardization of chemical nomenclature.
I think its less a single molecule than a novel approach to co-formulation. Formerly 98 (talk) 16:19, 18 September 2014 (UTC)
@Jytdog: On the risk of sounding nitpicky: We talk of ion channels but we don't say an ion channel is a single molecule as far as I'm aware. Something held together by H-bonds isn't a molecule. Otherwise water would be a huge macromolecule.
Also, solution in the GI tract isn't part of metabolism, and so valsartan and sacubitril aren't metabolites. --ἀνυπόδητος (talk) 16:28, 18 September 2014 (UTC)
I think the best analogy here is ciprofloxacin hydrochloride, which is a hydrated HCl salt. One can call ciprofloxacin a "molecule", and could arguably even call ciprofloxacin hydrochloride a molecule, since the cipro and the HCl form a salt. But the crystal structure shows the HCl salt of ciprofloxacin with water hydrogen bonded to it. I don't think anyone would call ciprofloxacin hydrate a new molecule. Formerly 98 (talk) 16:36, 18 September 2014 (UTC)

────────────────────────────────────────────────────────────────────────────────────────────────────Thank you Formerly, i was hoping you would weigh in. what i am hearing from you, is that: a) as a chemist you are not comfortable with their calling it a "single molecule"; b) you would call it a "complex salt" (by which I am guessing you are saying this is much more than just your typical ion + counter-ion salt). I did some more digging and found this:

  • Lili Feng, L et al. LCZ696: a dual-acting sodium supramolecular complex. Tetrahedron Letters 53 (2012) 275–276 (the authors are from Novartis)

which says:

Crystalline LCZ696, ... (CAS # 936623-90-4), is synthesized by dissolution of a NEP inhibitor (NEPi) ... and an angiotensin II (Ang II) receptor blocker (ARB) in the form of valsartan (Fig. 1). The subsequent addition of aqueous sodium hydroxide solution provides concurrently the sodium cations and water molecules necessary to induce crystallization of LCZ696. The crystal structure was determined using single-crystal X-ray diffraction. ... LCZ696 comprises six NEPi and six ARB moieties in their anionic forms, 18 penta- and hexa-coordinated sodium cations, and 15 water molecules providing a molecular formula of C288H330N36-O48Na18�15H2O (M.W. 5748.03). Such a 1:1 molecular ratio of NEPi to ARB is inherent as use of non-stoichiometric quantities of sodium hydroxide or either of the two moieties (±0.25 equiv) has no influence on the propensity to form LCZ696.

The chemical structure of LCZ696 can be described as a sodium supramolecular complex, with the sodium ions coordinated by oxygen ligands derived from 12 carboxylate groups and 18 carbonyl groups of the NEPi and ARB moieties, in addition to 13 out of the 15 water molecules (Fig. 2)....

LCZ696 is a hemipentahydrate white powder, which is morphologically composed of very thin hexagonal plates melting at around 138 �C. ... In the solid state, LCZ696 is very stable with no degradation being observed after 1 week at 50 �C—both for LCZ696 alone and in the presence of excipients—either in sealed containers or under 58% relative humidity. The stability of LCZ696 in aqueous solutions, however, shows a pH dependency. After 1 week at 50 �C in the pH range of 5–7, the concentration of degradation products, as measured by HPLC for the NEPi and ARB molecular moieties, was below 1.7%. Outside of this pH range, the solution stability quickly deteriorates, both at decreasing and increasing pH.

So there you go, from the horses mouth. what shall we call it? Jytdog (talk) 18:44, 18 September 2014 (UTC)

the more i think about it, yep this is just a fancy salt and the whole single molecule thing is scientific spin. i like the formulation " What about writing simply "LCZ696 is co-crystallised valsartan and sacubitril in a one-to-one ratio"? as originally proposed and will implement... thanks for discussing everybody. Jytdog (talk) 19:37, 18 September 2014 (UTC)
Thanks for the constructive discussion! The chemical information you dug up sounds really interesting; would you like to add it to the article? --ἀνυπόδητος (talk) 17:56, 19 September 2014 (UTC)
i don't much care about that but please feel free! Jytdog (talk) 18:52, 19 September 2014 (UTC)

Additional Paradigm clinical trial results published[edit]

So per Forbes, two papers, each with an accompanying editorial, have been published.

Need to figure out what kind of concise, non-conclusion-drawing content to rewrite from this - we still don't have any real secondary sources. So I don't see any point in discussing any of this in our article yet. Happy to discuss though. Jytdog (talk) 20:26, 8 January 2015 (UTC)


Drsciencewiki when you are asked nicely to please discuss on talk, please do so. Your change fucks up the drug box. Plus we don't need 6 citations to a trussed up press release in the article. Jytdog (talk) 21:22, 3 March 2015 (UTC)

there is now wild and crazy edit warring to keep the content, which i am using rollback for, as it is drug-box breaking vandalism. Above, we were saying that Novartis seems very intent on having everybody think of this as an NCE or something, and this bizarre behavior is kind of down that alley. Could be any kind of crazy person though. but look! trying so many times, and not talking at all. crazy and not-wikipedian. Jytdog (talk) 21:32, 3 March 2015 (UTC)
and i will now seek page protection. Jytdog (talk) 21:35, 3 March 2015 (UTC)
Jytdog first, I'm not in edit warring.I can't understand what u mean with "Your change fucks up the drug box". and u rollback my edits without telling what is wrong. Drsciencewiki (talk) 21:49, 3 March 2015 (UTC)
you are new to WP and have no idea what you are doing. You absolutely have been edit warring and what is shittier is that you did it through sockpuppets. If you continue to do that I will have you banned. Secondly, if you cannot see that your change breaks the drugbox, I don't know how to help you. I can tell you that every article has a "history" where you can see the versions. If you look at the version with your change, and without it, there is an obvious difference that any one who actually tries to look for it, can see. What is going on technically, is that having "combo" in the "type" field triggers the drugbox to be formatted in a way that shows both drugs; putting something else in that field formats it a different way so that neither drug shows. And thirdly, your sources do not add value. Jytdog (talk) 21:57, 3 March 2015 (UTC)