Talk:Surrogate endpoint

message: The Surrogate marker and Surrogate endpoint articles discuss identical topics.  I suggest this article be merged to Surrogate endpoint. Gak 01:35, 22 May 2007 (UTC)
replies: text: Went ahead and performed the merge. EAE (Holla!) 03:42, 16 January 2008 (UTC)
thread_title: Identical topics

message: I think this statement must be revised.
Could somebody give some feedback about this article?
--Truebreath (talk) 12:15, 11 May 2014 (UTC)
thread_title: Low importance of surrogate outcomes

message: I see someone deleting a source because it's primary.  No matter what MEDRS pushes, that makes me cringe -- and I'd argue that an article about surrogate endpoints is by definition about research, not treatment, so MEDRS should not apply to it.  Meanwhile, I see a bazillion examples like "Any hospitalization (composite outcome) / cost, disease burden".  What's the source for, say, this one?  Better a primary source than no source, that's for sure.  I can't even parse whether this is "hospitalization = surrogate, cost = real" or "cost = surrogate, disease burden = real".  Nor could I believe it either way. Wnt (talk) 16:46, 27 June 2014 (UTC)
replies: text: I have to disagree, this article discusses treatments and treatment options. Therefore we need to abide by WP:MEDRS when it comes to such statements. You are correct in that many of the statements here are purely research related, but those should also abide by MEDRS, which if paraphrased specifically states that clinically relevant statements need to follow certain rules. Therefor an article can comply with MEDRS, without all of the statements needing to be in accordance to the extra rules put on medical content. Each statement needs to be taken in context and even in a research related article do we need to stick to MEDRS when it applies. -- CFCF (talk · contribs · email) 17:30, 27 June 2014 (UTC)
replies: text: Well, to begin with, a surrogate endpoint is a concept, not a clinical observation in itself, and has broad applicability.  In ecological studies you can have things like "An evaluation of the relationship between salmon farm biomass, organic inputs to sediments, physicochemical changes associated with those inputs and the infaunal response – with emphasis on total sediment sulfides, total volatile solids, and oxidation reduction potential as surrogate endpoints for biological monitoring".  After all, the numbers of various organisms you can catch are absurdly variable due to experimental error and natural cycles, but simple chemical tests can sometimes predict the effect on them. Wnt (talk) 18:56, 27 June 2014 (UTC)
thread_title:  Sourcing for all the myriad examples? 

message: I've removed the following from the article:
:"Three meta epidemiologic studies found trials reporting surrogate primary outcomes were more likely to report larger treatment effects or more positive outcomes than trials reporting final patient relevant primary outcomes.[non-primary source needed][14][15][16] Trials using surrogate endpoints were more likely to report positive results, while those using mortality endpoints were less likely to be positive. Trials using surrogate endpoints (and disease-specific mortality) as an endpoint were more likely to be exclusively commercially funded.[non-primary source needed][17]
:...Only about one third of authors of randomised clinical trials that used a surrogate as a primary outcome reported clearly that the primary outcome was a surrogate. Better reporting was needed.[non-primary source needed][19]"
These are primary research articles that pass over important statistical issues and potential confounders.  To be specific:
*  The hurdle to showing statistical signficance is often higher in an outcomes trial. While the power of a trial using blood pressure as an endpoint is determined by the number of patients, the power of a trial examining cardiovascular outcomes is determined by the number of events, which is typically a low single digit percentage of the number of subjects in the trial. Thus part of the problem is the greater difficulty of demonstrating an effect based on low frequency binary events, and not simply the use of surrogate endpoints to cover up lack of efficacy as implied by the text.
* Similar confounding factors apply to the observation that trials sponsored by for profits are more likely to show superiority of new treatments than those by non-profits. While the non-profit organizations are indifferent to showing superiority, no sensible for profit company will run a head to head trial against an older treatment unless required to do so by regulatory authorities or confident of success.  Similarly, publication bias rears its ugly head here. This is an important problem, but one that is independent of the issue of surrogate endpoints, and thus off-topic.
* Reference 18 points out that commercial sponsors are more likely to use disease-specific mortality than all-cause mortality.  This is not, as implied by the article, a conspiracy to cover up bad results, but a requirement of the regulatory authorities. See for example: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071627.pdf
: "Sponsors should establish an independent cardiovascular endpoints committee to prospectively adjudicate, in a blinded fashion, cardiovascular events during all phase 2 and phase 3 trials. These events should include cardiovascular mortality, myocardial infarction, and stroke, and can include hospitalization for acute coronary syndrome, urgent revascularization procedures, and possibly other endpoints..."
Formerly 98 (talk) 22:12, 27 June 2014 (UTC)
thread_title:  Primary research sources on the use of surrogate, composite, and simple outcome endpoints 

message: "Coronary or cardiac revascularization (above before, below after) is a surrogate endpoint in lie of mortality in heart disease."
This is terribly wrong.
Cardiac revascularisation is an intervention; not a surrogate. The coronarography is a surrogate for cv events and mortality.
Please make the correction.
--Truebreath (talk) 14:46, 11 July 2014 (UTC)
thread_title: Figure problems

message: There are more than 250 biomarkers that are causally related to cardiovascular disease and that can be used as surrogates for prevention of cardiovascular disease.  Surrogates used for cardiovascular disease evolved from cholesterol, to LDL cholesterol, to HDL cholesterol, to high dense particles in LDL cholesterol, to crp and inflammatory parameters  and to visualisation of plaque burden etc.  
In the context of bypass graft procedures maybe the arteriografy is a good surrogate for the outcome. (the procedure itself is not a surrogate as wrongly added in the figure). The NUMBER of bypass procedures can be a part of a compound outcome as major cardiovascular events. So please correct the figure.
But few surrogates have been sufficiently evaluated to justify their use in developing drugs or making treatment decisions. (text IOM 2010)
But wat is the BEST surrogate for  an individual treatment , or food, or medical intervention , or medical devise? What surrogate predicts best the effect on hard outcomes?
The text of the 2010 US institute of medecine gives us examples:
The use of LDL as a surrogate endpoint for some cardiovascular outcomes , but not all cardiovascular outcomes  for statin drug interventions is supported by data. 
The use of LDL cholesterol as surrogate for cardiovascular outcomes  for other cardiovascular interventions and medications, foods, or supplements is not supported by data. HDL-C has not yet been qualified as a surrogate endpoint for cardiovascular risk because there is no evidence that HDL-raising interventions can improve outcomes.
The use of LDL cholesterol as cv surrogate for oestrogens of oestro-progestogen associations  and for ezetimibe is not supported by data. P164 P165
HDL cholesterol  and beta-carotene in serum as surrogates for cv disease  are not supported  by data . Niacin and derivatives didn’t influence cv  events in trials; neither did beta-carotene capsules; torcetrapib increased cv risk.
High sensitivity CRP as surrogate for cardiovascular outcomes is not supported by data .
Tumor response rate, tumor shrinkage, decreasing tumor size surrogates are not supported by data. There were inconsistent findings on tumor shrinkage and clinical benefit. The validity of the tests was a problem also. 
Bone density measurements are  a  surrogate outcome.  
Radiographic vertebral fractures is a composite outcome of a surrogate outcome (asymptomatic vertebral fractures) and clinical vertebral fractures . The latter being the meaningful clinical outcome that matters.
Nice 2008 “The definition of vertebral fractures is different in different trials. (outcome definition) (15 or 20% reduction in the height of one or more vertebrae). 20% was found to give more reliable results. Some studies used clinical (that is symptomatic) fractures as their endpoint whereas others used fractures that were identified radiographically. The majority of vertebral fractures (50–70%) do not come to clinical attention.  Nice 2008 http://www.nice.org.uk/nicemedia/live/11748/42447/42447.pdf
In the 3 cochrane analyses about the different biphosphonates they don't make the difference between both . The Canadian  therapeutic letter systematic review makes the difference and don't count vertebral fractures as clinical meaningful endpoint.
So bdm is a good  surrogate for secondary prevention of hip and wrist fractures in postmenopausal women for biphosphonates. During three years.  But til know not for clinical vertebral fractures. And not for primary prevention.
The alendronate cochrane analysis found only "gold" evidence for primary prevention of vertebral fractures (composite outcome), not for hip and wrist fractures, and not for clinical vertebral fractures.
For the same reason deep venous thromboflebitis (found by duplex scan eg) is a composite outcome, of clinically dvt and not clinicaly detected dvt; clinically dvt is the hard endpoint that matters for patients. See text on grade. And the same can be said about pulmonary embolism.
So there are no good or bad surrogates in se.  You must see a surrogate in the context wherein it is used. This is the third step in the surrogate evaluation process.
So I’ am not against use of surrogates for approval ,  I am not against innovation, I am not against the pharmaceutic industry, like you try to explain. I suggest you make the text on benefits of surrogates. But for me it is not necessary to make 500 lines about this.  I am convinced they are useful. You find them overall in medical literature. And during 38 years i have treated surrogate outcomes. So i suggest you make the part on hepatitis C and B. (I see you removed a cochrane review on treatment of hepatitis c, for reasons of copy pasting. I thought wikipedia tried to collaborate more with the cochrane collaboration. I almost always use their summaries, and copy past them, because they are so easy to understand. Is this forbidden????Can we not copy paste from open sources as plos one????)
But recent studies have challenged the assumption that reliance on surrogates can accurately predict the effect of treatment on hard outcomes. There are the oral hypoglycaemic drugs that reduce HbA1c but increase the risk of cardiovascular events,  antihypertensive drugs that do not reduce the risk of stroke,  and drugs that improve cholesterol profiles but do not reduce cardiovascular events. Explanations for such phenomena include unwanted effects of the drug or an incomplete understanding of the pathophysiology of the disease.
So when the FDA considers each blood pressure lowering medication as healthy, this is not evidence based.
So when the FDA says it is unethical to do trials against placebo for a ca antagonists they are right;  but you can do trials against hygroton or against an ace inhibitor. So please remove that.
It is in the interest of  the Pharmaceutical industry and the overall health of people that the right surrogate is used in the right context.
The science about this has recently been developed after 2000, and is still going on.
This discussion is of high interest for patients and doctors. For patients  it contributes to de-medicalisation. For doctors it stimulates evidence based thinking to take the right decisions for individual patients.  Am I treating a patient or a surrogate?
“The FDA’s current regulatory authority is not sufficient. Inadequate fulfillment of postmarketing studies and incomplete understanding of how consumers interpret food and dietary supplement claims prevent robust protection of public health. “ IOM P 197
Can we agree on what precedes? Then we can go further--Truebreath (talk) 15:30, 11 July 2014 (UTC)
thread_title: Good and bad surrogates? or surrogates in the context of treatment? a first response to the point of views of “Formerly 98”

message: Formerly 98 said: "Systematic reviews should not present surrogate outcome data as their primary analysis" is clearly not mainstream as 90% of published meta analyses do exactly that.”  But a meta analysis is not the same as a “systematic review and meta analysis”. In the analyses of failed surrogate outcomes I tried to find systematic reviews. Those don't look only at the surrogate but also at the clinical endpoints that matter (efficacy AND efficiency outcomes) AND to the safety outcomes. See cochrane
“Systematic review (synonym: systematic overview): A review of a clearly formulated question that uses systematic and explicit methods to identify, select and critically appraise relevant research, and to collect and analyse data from the studies that are included in the review. Statistical methods (meta-analysis) may or may not be used to analyse and summarise the results of the included studies. “
And
“A crucial step in a cochrane systematic review is the specification of all patient-important outcomes relevant to the intervention strategies under comparison .” Cochrane handbook.
Formerly 98 said: “problems with rimonabant are unrelated to the subject of surrogate endpoints. It was pulled for CNS side effects, which are unrelated to the question of whether weight loss was an acceptable surrogate for cardiovascular disaese”  
The  hardest endpoint is mortality.
Rimonobant was not found to decrease cv mortality or cv events;  there was found a higher risk of depression and suicide., two clinically meaningfull endpoints, related to morbidity and mortality.  So ema found the benefits didn't outweigh the harms. So (small) weight loss is a bad surrogate endpoint for rimonobant.   Surrogate endpoints are not absolute, you have to see them in the particular context.  Considerable weight loss was a good surrogate for bariatric procedures for cv events as  described in the text.
Formerly said: “Teriparatide is criticized even though it used a "real" endpoint for in its trials. It reduced vertebral fractures by nearly 2/3's (From 14.3% to 5.0%), and reduced combined non-vertebral fractures by half (5.5% vs. 2.6%).” 
As said before vertebral fractures are not a “real” endpoint but a surrogate composite endpoint. It is a composite of clinically radiological vertebral fractures and asymptomatic radiological fractures.  Hip fracture was not reduced.  You should always describe absolute risk decrease and NNT in your viewpoints, not relative. 
Cochrane doesn't have a combined systematic review on all biphosphonates ; wrist and hip fractures and clinically vertebral fractures are unequivocally  hard endpoints.  Clinically vertebral fractures are only occasionally reported in the 3 cochrane analysis.  So the conclusion  of the therapeutics letter systematic review “ in secondary prevention, the small benefits of bisphosphonates likely outweigh the harms during the first 3 years of therapy, but harms likely outweigh benefits for durations greater than 3 years “ seems right.
Formerly 98 said “The problems throughout are WP:OR, WP:OS and WP:COAT. “
Wikipedia: original research: the item of problems with surrogate outcome is not original research by me; it was found throughout searches about the item  in systematic reviews found  by a search strategy essentialy based on  Dare, trip database and cochrane.  I tried to confront them with Nice  and other guidelines in an international context. I never give my personnel opinion about the evidence . I sometimes confront evidence.  I found it interesting to confront two systematic revies of biphosphonates. The reader  (patients and doctors) should make individual decisions about this evidence. I try always to refer to cochrane summaries if they exist, because they are easy readable by wikipedia users.
Wikipedia "oversight", (the power to suppress edits, is entrusted to a restricted number of users,) .
I don't care some edits were deleted  because they were not from secundairy sources. But the item of  surrogates is not so easy as let say ciprofloxacin. It involves the whole area of medecine. Finding relyable secundary sources about the item is not easy. 
One example of a deletion was the removal in the lead of an editorial about evidence based making of mini reviews in the field of haematology.
I removed it and added excerpts from the cochrane handbook of systematic reviews, which explained exactly the same. Maybe this handbook too is not a secundary source?
Wikipedia Coatrack (articles run against the fundamental neutral point of view policy: in particular the requirement that articles be balanced) .  
I agree and suggest you write the part benefits of surrogates.  Maybe beginning with looking at the benefits of hepatitis C treatments, because i had problems to find them in hepatitis B and in hepatitis C. So i have put this part in the problems section. If you find better proof you change it to the benefits.
To make the text “more balanced” formerly 98 made a table, in which he describes 14 medications approved in 2008 on basis of surrogate enpoints, and then he looks for the actual situation on the meaningfull clinical outcome. 
Why formerly takes 2008? Why does he make a table full of medications that most readers and doctors don't  know?
The only possible breakthrough medication is the arthemeter combination, included in the WHO essential medecines and maybe etravirine which  is an additional option for HIV-infected patients with multiple treatment failure. The rest are me too medications (ca antagonists, statins) and orphin drugs for which we can maybe wait until the end of my life to have clinical meaningfull endpoints, because they are so seldom. So this table ads nothing to the point of benefits of surrogate endpoints. So i ask you to delete it. There are already enough examples of surrogate endpoints from medications that people know.
Another example of deletion by formerly 98 was:
"Three meta epidemiologic studies found trials reporting surrogate primary outcomes were more likely to report larger treatment effects or more positive outcomes than trials reporting final patient relevant primary outcomes.[non-primary source needed][14][15][16] Trials using surrogate endpoints were more likely to report positive results, while those using mortality endpoints were less likely to be positive. Trials using surrogate endpoints (and disease-specific mortality) as an endpoint were more likely to be exclusively commercially funded." He rejected those studies with his own theories as “statistical significance” and “confounders” without proof.  Only to refute them.  This is pure speculation.  This is not evidence based.
The facts are right or not; it is not important what formerly 98 thinks about those facts or why tose facts are not relevant.
Those articles were found in  BMJ and   by using searches with trip database.
They confer with data found in composite outcomes “that the effect is smallest for the most important component and biggest for the less important components”., which was well mentioned in a systematic review.
Formerly 98 found “Reference 18 points out that commercial sponsors are more likely to use disease-specific mortality than all-cause mortality.  This is not, as implied by the article, a conspiracy to cover up bad results, but a requirement of the regulatory authorities .”
The text in wikipedia  was very neutral:  “Trials using surrogate endpoints (and disease-specific mortality) as an endpoint were more likely to be exclusively commercially funded. “ Those were facts stated in the cohort of trials. No conspiracy theories at all.
A wikipedia editor (formerly 98?) found there were not enough references in the text of examples of surrogate outcomes; they didn't notice the 150 cross references within wikipedia. So i added some 150 references most from systematic cochrane reviews. But still the heading find not enough references. So please can you remove that heading. And please correct the figure.
About all those things i want to have a neutral view from another wikipedia editor. 
I have made thousands of contributions to wikipedia ; i never had that kind of personal attacs. And if there were critics always there was found  a solution.
Formerly 98 attacks my personal integrity, by making allusions of conspiracy, and  of points of view against the pharmaceutical industry. This must stop.
Living in hope.
Yours sincerely 
--Truebreath (talk) 19:19, 15 July 2014 (UTC)
thread_title: Point by point response to the point of views of “Formerly 98”. Second response.

message: The whole content was deleted because "there was proof that hepatitis B prevented hepatocellular carcinoma in a 2009 meta analysis."
You can find this meta analysis and a discussion about it here:
http://ebm.bmj.com/content/14/3/86.extract
It was a metaanalysis of 3 rcts, and 16 cohort studies of which 10 were of good quality. So the outcome of such analysis can only be hypothesis forming.
The commentary from ebm.bmj says: "pivotal trials have found no evidence on death, livercancer or liver transplantation. The metaanalysis suggests a potential benefit of treatment of hepatitis B on liver cancer."
Another meta analysis was given
http://www.ncbi.nlm.nih.gov/pubmed/23713520
the meta analysis included 6 "studies" (not trials) about lamivudine, which found a lower risk of liver cancer.
So again this is suggestive for an effect. But no proof.
There was only one trial included on lamivudine:  "In the only 2004 randomized, controlled clinical trial including 651 chronic hepatitis B patients (58% HBeAg positive) with biopsy-proven cirrhosis or advanced fibrosis, lamivudine was found to significantly reduce the risk of HCC compared to placebo (3.9% vs 7.4%, P = 0.047)[37]. When HCC cases diagnosed during the first year of treatment were excluded, the risk reduction was marginally non-significant (P = 0.052). So this is a close call....and the study was terminated early after a mean duration of 32.4 mo because of significant beneficial effects in the treatment group (7.8% developed cirrhosis complications vs 17.7% in the placebo group, P = 0.001).
http://www.ncbi.nlm.nih.gov/pubmed/15470215 
Pooled data from 49 studies found: 
However, HCC still develops at a rate of 1.3 per 100 patient years in CHB patients receiving an oral anti-viral agent. This finding highlights the need for continued HCC surveillance, particularly in CHB patients with inadequate viral suppression, older age and cirrhosis.
On the contrary a 2013systematic review in BMJ found :
http://www.ncbi.nlm.nih.gov/pubmed/23945731
Randomised trials found no effect of antiviral therapy on HCC or mortality. Cohort studies found that antiviral therapy increased the risk of HCC (risk ratio 1.43; 95% CI 1.06 to 1.95), whereas case-control studies found a decreased risk of HCC in the intervention group (risk ratio 0.69; 95% CI 0.54 to 0.88). There was a clear difference between the results of RCTs and observational studies (test for subgroup differences, p<0.001). Antiviral therapy did not affect mortality in cohort studies, but reduced mortality in case-control studies (relative risk 0.71; 95% CI 0.54 to 0.93; test for subgroup differences, p=0.406).
CONCLUSIONS:
The effect of antiviral therapy on clinical outcomes in HBV remains to be established. Although there was a positive effect in the sensitivity analyses, the strength of the evidence does not allow for extrapolation to clinical practice as research design plays an essential role in the overall assessment.
So i put back my text and ad the results of the systematic review.
--Truebreath (talk) 12:05, 12 July 2014 (UTC)
thread_title: Deleting content about hepatitis B by "formerly 98"

message: Analysis Validates Use of PFS As Surrogate Endpoint in Sarcoma Trials. March 2016 Seems useful and relevant but given the edit warring above I hesitate to edit the article. Source says "In an analysis of surrogacy, the researchers found a highly significant correlation between OS and PFS (R = 0.61), as well as between RR and OS (R = 0.51)." Not clear what R would be an acceptable minimum. Are there guidelines on what correlation is required (eg by FDA) in different circumstances ? - Rod57 (talk) 06:17, 10 March 2016 (UTC)
thread_title:  Source on use of surrogate endpoints in soft-tissue sarcoma clinical trials 

message: Article says "A correlate does not make a surrogate. It is a common misconception that if an outcome is a correlate (that is, correlated with the true clinical outcome) it can be used as a valid surrogate end point (that is, a replacement for the true clinical outcome). However, proper justification for such replacement requires that the effect of the intervention on the surrogate end point predicts the effect on the clinical outcome—a much stronger condition than correlation." but this seems nonsense and needs to be better explained.Analysis Validates Use of PFS As Surrogate Endpoint in Sarcoma Trials. March 2016 (quoted in the section above) seems to explicitly evaluate surrogates based on their correlation with outcomes. Help! - Rod57 (talk) 06:40, 10 March 2016 (UTC)
thread_title:  Does correlation make a surrogate 

message: Article says " While elevated cholesterol levels increase the likelihood for heart disease, the relationship is not linear - many people with normal cholesterol develop heart disease, and many with high cholesterol do not" seems internally inconsistent. By "not linear" perhaps "poorly correlated" is meant. - Can someone clarify ? - Rod57 (talk) 06:45, 10 March 2016 (UTC)
thread_title:  "Relationship is not linear" - is confusing 

message: FDA Slammed for Rush to Approval of Cancer Drugs - Analysis questions use of surrogate endpoints. May 2016. Does it say anything new ? - Rod57 (talk) 16:58, 4 June 2016 (UTC)
thread_title:  New discussion of FDA use of surrogate endpoints