Talk:Bardoxolone methyl

Multiple Issues

Noticed several areas for improvement of the article. First, citations are currently included as external links (see WP:EXTERNAL). This is verboten; they should be formatted as footnoted citations and included in a reference list at the end of the article. Second, the article relies too much on primary source research papers and, worse, company press releases (highly promotional); reliable secondary sources (independent review articles, expert medical organization consensus statements, etc.) that meet WP:MEDRS should form the basic narrative. Third, the article feels somewhat promotional in tone; for example discussing the potential for the compound to have therapeutic effects that have not yet been substantiated. It's not even clear if the product has been approved for any medical condition, and if it hasn't, the article needs to be toned down considerably. Also, as I understand it, clinical trials evaluating the product were terminated due to toxicity issues. This should be included in the lead. This is a drug candidate that failed during clinical development, but the article doesn't make that clear. Rhode Island Red (talk) 02:03, 29 September 2014 (UTC)

The citations have been updated to be footnoted citations in the reference list.

References were added to the Pulmonary Hypertension Association website, the primary advocacy group for the disease. The press release from KHK has been removed and replaced with a news update from Reuters. Please let me know if this is acceptable.

The termination of the BEACON clinical trial is stated under the Phase 3 heading. This does not mean the drug failed in clinical development, but that a trial had to be stopped. Details around what happened in the trial are detailed in the post-hoc analysis section and in the referenced journal articles. With these details published in the American Journal of Nephrology at the provided reference, and an open IND (after FDA review) for Pulmonary Arterial Hypertension (see provided reference to clinicaltrials.gov), the information is felt to be accurate and balanced to reflect that development of bardoxolone methyl is still ongoing.

Thank you, further thoughts are appreciated. — Preceding unsigned comment added by Nrf2-fan (talk • contribs) 15:57, 29 September 2014 (UTC)

I didn't notice any link to the Pulmonary Hypertension Association website. Can you please point out where this was added. The blurb from Reuters is basically just a press release. As I pointed out, in general the article relies too much on primary sources and sources connected with the company. Secondary independent references should be the basis for the narrative about the drug.

When a drug shows unacceptable toxicity in a phase 3 trial and the trial is terminated as a result, it is most definitely considered a failure. The details of this failed trial are buried deep in the article but this is probably the most important detail and should be featured prominently in the lead. As far as I can gather, bardoxolone has not been approved for the treatment of any disease, but the article does not convey that at all; quite the opposite -- it seems like it was written by the company to portray the product in as positive a light as possible, which violates WP:NPOV and WP:PROMO. The story of the drug so far is that it showed interesting preliminary results in preclinical and early-stage clinical trials but failed in advanced trials and has since not been proven effective for the treatment of any medical condition. Rhode Island Red (talk) 18:27, 29 September 2014 (UTC)

The Pulmonary Hypertension Association (PHA) link is reference #12. I have updated the first paragraph per your suggestion, describing bardoxolone methyl as experimental but indicating that it is still under clinical development. References 6 and 8 are review articles that serve as secondary sources.

You originally described #12 as a reference to "the Pulmonary Hypertension Association website, the primary advocacy group for the disease". It is in fact simply an in vitro study published in the journal Clinical Cancer Research; it is not endorsed by the Pulmonary Hypertension Association nor does it have anything to do with patient advocacy. It may be OK to cite it with the usual caveats about WP:PRIMARY but there's no need to gild the lily. Rhode Island Red (talk) 20:21, 29 September 2014 (UTC)

There seems to be an error for the Reference and External links headings. Could you please advise? Thanks! — Preceding unsigned comment added by Nrf2-fan (talk • contribs) 20:05, 29 September 2014 (UTC)

Please provide with further guidance. I updated the first paragraph to more specifically defined the patient population that was at risk, as described in the AJN article. This is a fact.Nrf2-fan (talk) 20:14, 29 September 2014 (UTC)

Also please remove tags, as I think the issues have been adequately addressed. Do you agree? Specific recommendations? Also, the language has been updated so that a literate Wikipedia user can understand. Could you please remove the intricate detail tag?Nrf2-fan (talk) 20:17, 29 September 2014 (UTC)

The tags should remain until the issues have been resolved. The article still relies almost exclusively on primary sources, associated for the most part with the manufacturer (e.g., press releases and company-sponsored/authored research). The article is overly technical in places and not ideal for the WP layman audience (think encyclopedia not technical article). Many of the research details are superfluous. Overall, there is a tendency to exaggerate positive aspects about the product and downplay negatives, but the failure of the drug during clinical development is probably the single most noteworthy feature of bardoxolone to date. The article overemphasizes the importance of pre-clinical and early-phase clinical studies, which are largely irrelevant since the drug failed in advanced clinical testing. Similarly, the section on the post-hoc analysis seems to have been given undue weight -- more weight than the original phase 3 trial itself. Planned studies are relatively trivial and warrant nothing more than passing mention.

Also, the material you added in the lead was not consistent with the cited sources and come across as WP:WEASEL. I removed the material accordingly and you have now reverted me twice. If you do it again instead of trying to resolve the issue on the Talk page, you could end up being blocked. I also see potential issues here with WP:SPA and WP:COI so you might want to take a step back. Rhode Island Red (talk) 20:48, 29 September 2014 (UTC)

Sorry, new at this. Could you please provide language within this Talk page, so we can try to come to a middle ground? Thank you. — Preceding unsigned comment added by Nrf2-fan (talk • contribs) 20:56, 29 September 2014 (UTC)

I've provided plenty of detailed guidance so far. I don't have time today to completely rewrite the article, especially with you making a bunch of intervening edits while I'm in the process of editing, and edit warring. What's the hurry? WP:COI is also a concern. In the meantime, if you have any specific questions, post them here and I will do my best to answer them. Rhode Island Red (talk) 21:04, 29 September 2014 (UTC)

I think it would be appropriate to change that sentence in the first paragraph to the following: "A phase 3 clinical trial evaluating bardoxolone methyl for the treatment of chronic kidney disease (CKD) was terminated in October 2012 after a subset of patients, with underlying heart failure, treated with the drug were found upon post-hoc analyses to have experienced a higher rate of heart-related adverse events, including heart failure, hospitalizations and deaths" Please see the 4th paragraph of the Introduction in the following well-respected peer review journal with authors highly respected in the field of nephrology. http://www.karger.com/Article/FullText/362906

Would you also think it would appropriate to add the following to the "Phase 3" section. "Further, among patients with type 2 diabetes and advanced stage 4 CKD, bardoxolone methyl did not reduce the risk of end stage renal disease or cardiovascular death." Nrf2-fan (talk) 13:24, 30 September 2014 (UTC)

I would also like to add that early clinical studies have demonstrated Nrf2 and NF-KB activity in the first paragraph. Data from the article at the following location supports that: http://clincancerres.aacrjournals.org/content/18/12/3396.longNrf2-fan (talk) 14:00, 30 September 2014 (UTC)

With respect to the lead, the two references cited in which the phase 3 clinical trial failure are described do not refer to a subset of sensitive patients. The key point is that the trial was terminated due to adverse events, deaths, etc. The detail you refer to, from a subsequent retrospective analysis conducted by the manufacturer, is currently included in the overly long and unduly weighted section that describes the post-hoc analysis (and incidentally, that section needs to be trimmed considerably). The lead is intended to summarize key points, but should not delve into minutiae like the retrospective post-hoc analysis or imply that the original study said something that it didn't, which would violate WP:SYNTH.

As for statement you proposed for the Phase 3 section, on which reference is this supposed to be based?

Lastly, with respect to the proposed statement about Nrf2 and NF-KB, I'll have a look at the article you mentioned by Hong et al. (2012) and get back to you on that ASAP. Rhode Island Red (talk) 15:44, 30 September 2014 (UTC)

Thoughts on the following for the post-hoc paragraph:

An increase in heart failure events was the major finding that led to the early termination of the BEACON clinical trial: 96/1,088 (8.8%) bardoxolone methyl-treated patients versus 55/1,097 (5.0%) placebo-treated patients.[1] Post-hoc analyses identified prior hospitalization for heart failure and baseline brain natriuretic peptide (BNP), a marker of fluid retention, as predictors of heart failure hospitalizations in BEACON. For patients without these baseline characteristics, the risk for heart failure among bardoxolone methyl- and placebo-treated patients was similar. The exclusion of patients with these risk factors would have balanced the number of serious adverse events between treatment groups. [5] Moreover, the clinical phenotype of fluid overload and heart failure in BEACON was similar to that observed with endothelin receptor antagonists in advanced CKD patients, and preclinical data has demonstrated that bardoxolone methyl can modify endothelin signaling.

Phase 3 study reference is here: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1306033Nrf2-fan (talk) 16:03, 30 September 2014 (UTC)

To make it encyclopedic and audience appropriate, I'd skip the last two sentences and also the data about proportions of patients. Also, this information should be in the phase 3 trial section and not highlighted in a separate section as this gives WP:UNDUE to the post-hoc analysis. I have modified the text to the article accordingly. Again, it should be pointed out that those with a WP:COI should not edit the article directly but can instead participate on the Talk page. Rhode Island Red (talk) 16:38, 30 September 2014 (UTC)

Reference #s 6 and 16 are review articles (secondary sources), suggest removal of "primary sources" tag What do you think needs to specifically be added to remove the other tag?Nrf2-fan (talk) 18:29, 30 September 2014 (UTC)

References #6 and #16 are both connected with Reata; independent sources would be preferable. I'll dig around and see if there are any good independent secondary sources. I'm also going through some of the primary source studies now and working on smoothing out the language in the article. When that's done, the primary sources tag can probably be removed. I don't necessarily object to the use of primary sources, but if they are to be used, great caution must be exercised to ensure that they are represented with a NPOV. Rhode Island Red (talk) 20:12, 30 September 2014 (UTC)

Looks great, thank you for the help.Nrf2-fan (talk) 21:27, 30 September 2014 (UTC)

Adding this sentence is not unnecessary in the lead. It is important context recently published about what was learned from the clinical trial with bardoxolone methyl. Please put it back in.

Elevated baseline b-type natriuretic peptide (BNP) and prior hospitalization for heart failure were later identified as risk factors for prediciton of heart failure events.[1] Future trials will require exclusion of patients with these risk factors. Nrf2-fan (talk) 17:27, 16 October 2014 (UTC)

The critical point is that the compound failed in phase 3 and the trial was stopped due to AEs. The post facto retrospective analysis of potential risk factors for AEs, conducted by Reata, is mentioned in the body text but is not critical for the lead. It's a relatively trivial detail and adding it in the lead seems like an attempt to whitewash the major point regarding the failed clinical trials. Rhode Island Red (talk) 19:16, 16 October 2014 (UTC)

January 2017 Page Update

Please provide thoughts on the following updates to the page

• End of First Paragraph: "Clinical development of bardoxolone methyl has continued in a phase 3 study for pulmonary arterial hypertension."
• Last Sentence in Pulmonary Hypertension Section: Update to: "In January 2016, Reata initiated the LARIAT study, a placebo-controlled, multicenter phase 2 clinical trial, to assess the effects of bardoxolone methyl in PAH. In October 2016, Reata also imitated the CATALYST study, a placebo-controlled, multicenter phase 3 clinical trial, in patients with connective tissue-associated PAH."
• New Section: Continued Development of Bardoxolone in CKD patients with type 2 diabetes; "In 2014, Kyowa Hakko Kirin initiated the phase 2 TSUKABI study to evaluate the safety and efficacy of bardoxolone in patients with CKD and type 2 diabetes."
• Keep recent additions that were removed to final Mechanisms section

--Nrf2-fan (talk) 14:07, 23 January 2017 (UTC)

Studies that are planned, in progress, or otherwise unpublished are not notable for an encyclopedia. Rhode Island Red (talk) 15:45, 23 January 2017 (UTC)

There are a multitude of instances on Wikipedia where clinical studies with press release or meeting abstract references are listed for drugs under development. Thus, there is considerable precedent on Wikipedia for such information. Allopregnanolone, Ganaxolone, Sacituzumab govitecan, Risankizumab, Clazakizumab, Guselkumab, Mavrilimumab, Otelixizumab, to name just a few... Why do you single out bardoxolone methyl? --Nrf2-fan (talk) 17:30, 23 January 2017 (UTC)

It probably doesn't belong in those articles either. Articles on medical subjects should follow WP:MEDRS. A press release announcing a clinical trial falls under the category of WP:NOTNEWS and including it would be WP:PROMO (see also WP:CRYSTAL which states: "Wikipedia is not a collection of product announcements "). It is not a noteworthy detail, as it's possible that such trials may not actually be initiated, will cease before completion, may produce negative results, and may never be published. What is encyclopedic and of scientific importance is what completed studies actually show, and for that we ideally rely on third-party WP:MEDRS. Rhode Island Red (talk) 18:07, 23 January 2017 (UTC)

I also feel compelled to advise you about WP's policies on conflict of interest and single-purpose accounts and to ask you to make sure to comply, which would entail not editing the article directly. Rhode Island Red (talk) 18:11, 23 January 2017 (UTC)

Press Releases and Meeting Abstracts Are Not WP:MEDRS

Please note that press releases and meeting abstracts do not satisfy WP:MEDRS, which states:

"Press releases, newsletters, advocacy and self-help publications, blogs and other websites, and other sources contain a wide range of biomedical information ranging from factual to fraudulent, with a high percentage being of low quality. Conference abstracts present incomplete and unpublished data and undergo varying levels of review; they are often unreviewed and their initial conclusions may have changed dramatically if and when the data are finally ready for publication. Consequently, they are usually poor sources..."

Hence this edit[2] has been reverted--twice now. Please heed the policy above and do not re-add this material to the article. Rhode Island Red (talk) 17:59, 5 May 2017 (UTC)

Another relevant WP guideline statement (from WP:SCIRS):

"Cutting edge science is built on the foundation of previous research, and paradigms almost always change only slowly. Preliminary results, whether reported in the popular press, a conference abstract, or a peer-reviewed journal, are a form of anecdote and generally fall below the minimum requirements of reliable science sources….Conference abstracts are often incomplete and preliminary, and may be contradicted if and when the data are published; they should be avoided." Rhode Island Red (talk) 22:01, 5 May 2017 (UTC)