 |
 |
Looks like there is a protocol published for a Cochrane Review - http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010587/pdf . Interestingly they are planning to include DAA vs placebo trials. Not sure that's a good idea given we know IFN based regimens are somewhat effective. I can't see a timeline for completion of this review but may not be looking in the right place? Best wishes, Tom On 16 April 2014 16:06, Poses, Roy <[log in to unmask]> wrote: > Thanks for all the comments, only some of which are below. > > I have only seen extreme optimism about the drugs in the media and the > journal articles I have managed to read. I have seen NO skepticism at all > about the drugs or the evidence supporting them. The only concerns are > about the price. But again, if the drugs offer miraculous cures without > any serious downside, who would really contest the price ;-) ? > > I am neither an infectious disease nor a liver specialist, so am not fully > acquainted with all the details, especially about particular virus types. > So I am not the ideal person to take the lead on this particular issue.\ > > Yet I am concerned that this horse is already out of the barn, and there > already is a consensus that the drugs are near miraculous, never mind the > evidence. > > The Cochrane and EBH groups may include the only people who might bring > some evidence-based skepticism to address this issue, so my hope was to > alert you all, and hope some of you will have a closer look before the > horse has run too far. > > > > > On Wed, Apr 16, 2014 at 8:48 AM, Tom Yates <[log in to unmask]>wrote: > >> In the Afdahl study, with the 90+% SVR rates, they were not looking at Sofosbuvir >> alone, as they did in the head to head trial, but at various Ledipasvir-Sofosbuvir >> based regimens in patients that had previously failed IFN/RBV. I agree >> patient selection is also likely to be important in explaining these >> results but I don't know enough about HCV to know whether this might >> explain the very high SVR rates described in the latter study. I am yet to >> speak to an infectious disease specialist who isn't excited by these >> results. >> >> Great discussion, >> Tom >> >> >> On 16 April 2014 13:29, Poses, Roy <[log in to unmask]> wrote: >> >>> But am I the only one who finds it very strange that in the only >>> comparison of sofosbuvir with another drug (peg-interferon) the SVR for >>> sofosbuvir (and the comparator) was about 67% 12 weeks after therapy, but >>> in all the other studies of sofosbuvir the SVR was much higher? >>> >>> I note that in every study I have looked at, the inclusion and exclusion >>> criteria were extremely extensive, suggesting that the studies were done on >>> the healthiest of the healthy patients (still with HCV). My concern is >>> that the very high SVR's in studies in which sofosbuvir was not compared to >>> other drugs (or placebo) reflect patient prognoses rather than treatment, >>> but that these very high SVR's are being used to promote the ridiculously >>> high price of the drug. >>> >>> >>> On Wed, Apr 16, 2014 at 8:01 AM, Ansari, Mohammed <[log in to unmask]>wrote: >>> >>>> >>>> *I think in this particular case I find the FDA flexibility >>>> reasonable. Its true that we may not have a comparator that is standard of >>>> care...but we do have historical knowledge, and expectations, of change in >>>> outcomes in response to standard of care. If we have no major concerns >>>> about the study population and study validity, then we know the standard of >>>> care counterfactual in terms of virologic response from valid RCTs - our >>>> response benchmark. That outcomes are soft and not hard is altogether >>>> another point. * >>>> >>>> >>>> >>>> *From:* Evidence based health (EBH) [mailto: >>>> [log in to unmask]] *On Behalf Of *Tom Yates >>>> *Sent:* Wednesday, April 16, 2014 3:34 AM >>>> *To:* [log in to unmask] >>>> *Subject:* Re: Questions about new, heavily hyped treatments for >>>> hepatitis C >>>> >>>> >>>> >>>> I agree and it is regrettable that it was not done right the first >>>> time. I now worry, however, that we are approaching the point where >>>> sufficient non RCT data is accumulating and public perception is such that >>>> it would be very difficult to do the proper head to head clinical trial. Is >>>> anyone in the HCV word voicing concerns about this? I hear only optimism. >>>> >>>> >>>> >>>> Best wishes, >>>> >>>> Tom >>>> >>>> >>>> >>>> On 15 April 2014 19:59, Poses, Roy <[log in to unmask]> wrote: >>>> >>>> It seems to me that a controlled trial only tells you about the >>>> outcomes of the treatment compared to the comparator. So if the comparator >>>> is, say, just a different dose or duration of the same drug, all that trial >>>> can say is whether there is a difference between the doses or durations. >>>> >>>> To prove that the drug is better than the standard of care, one must >>>> compare it to the standard of care, no? >>>> >>>> But from what I can tell, in the case of Sovaldi/ sofosbuvir, the only >>>> comparison to the standard of care at best only proved "non-inferiority," >>>> but did not prove overall superiority (of benefits vs harms). >>>> >>>> >>>> >>>> On Tue, Apr 15, 2014 at 7:09 AM, Tom Yates <[log in to unmask]> >>>> wrote: >>>> >>>> Hi Roy, >>>> >>>> >>>> >>>> I think these are really important issues. I am told there is another >>>> head to head study vs IFN called BOSON but can't find the paper. >>>> >>>> >>>> >>>> A recent editorial in the NEJM contained the following paragraph ( >>>> http://www.nejm.org/doi/full/10.1056/NEJMp1400986)... >>>> >>>> >>>> >>>> *'...additional steps were required to get from these >>>> interferon-tethered regimens to trials of investigational DAAs in >>>> combination. Traditional study designs had, until recently, used a >>>> standard-of-care comparator for new agents, which in the case of HCV meant >>>> using an interferon-based therapy in the control group -- an unappealing >>>> prospect for many patients. Buoyed by the success of combination HIV >>>> therapies and the knowledge that resistance variants in HCV were not >>>> predicted to persist as they do in HIV, the Food and Drug Administration >>>> agreed to permit phase 2 trials to use new combinations of HCV DAAs without >>>> requiring a standard-of-care comparator. This decision proved catalytic. >>>> Because of the short durations of, and rapid enrollment in, these studies, >>>> the pace of ensuing clinical drug development has been breathtaking.'* >>>> >>>> >>>> >>>> I find this sentiment worrying but I'm told there are real difficulties >>>> in recruiting patients to trials including IFN based regimens now. The side >>>> effects of IFN are, I understand, miserable and most patients are aware of >>>> the existence of alternatives. There is a good chance that patients may >>>> enroll in such studies hoping to be randomised to DAA and then not take >>>> their treatment if randomised to IFN, meaning trials provide good evidence >>>> on effectiveness but poor data on relative efficacy. >>>> >>>> >>>> >>>> What trials do you think we should be calling for? The Afdahl trial you >>>> reference is interesting, recruiting people who had previously failed IFN >>>> based therapy. Do we still have equipoise? Are virological outcomes ok? I >>>> would have thought that any licensing should be conditional on ongoing >>>> follow up (presumably for many years) to get clinical outcomes. >>>> >>>> >>>> >>>> It would be nice to have some non industry trials. There is a notable >>>> absence of trials in 'hard to reach' groups - e.g. injecting drug users, >>>> people with alcohol dependence, etc. There may be an opening there for >>>> rigorous independently conducted studies with highly relevant outcomes. >>>> What should such studies look like? >>>> >>>> >>>> >>>> All the best, >>>> >>>> Tom >>>> >>>> >>>> >>>> On 13 April 2014 20:00, Poses, Roy <[log in to unmask]> wrote: >>>> >>>> I wondered if anyone on the list had taken a close look on the (at >>>> least published) clinical literature on sofosbuvir (Solavdi - Gilead), >>>> which is now currently being heavily promoted as practically a miracle cure >>>> for hepatitis C, and is prices at $1000/ pill, $84,000 per 12 week course >>>> of therapy in the US? (See: >>>> http://hcrenewal.blogspot.com/2014/03/too-good-to-be-true-sovaldi-kerfuffle.html >>>> ) >>>> >>>> We reviewed the May, 2013 article on the drug that appeared in the >>>> NEJM(1) for our journal club. Briefly, this was a non-inferiority trial of >>>> sofosbuvir plus ribavirin vs peg-interferon vs ribavirin. The sustained >>>> viral response rates for both were numerically the same at 12 weeks after >>>> therapy finished (67%). The patient population had multiple inclusion and >>>> exclusion criteria, buried in an appendix, that suggested a lack of >>>> generalizability. The sofosbuvir treated patients had lower rates of >>>> bothersome adverse effects than the peg-interferon treated patients, but >>>> these rates were hardly negligible. Also, by perusing the appendix, one >>>> could find that the severe adverse effect plus death rate was higher in the >>>> sofosbuvir group than in the peg-interferon group, but the difference was >>>> not statistically tested. Of course, the study did not follow patients >>>> long-term (for a very long-term disease) and did not assess any clinical >>>> outcomes. Most particularly, it did not assess whether treatment prevented >>>> any of the know complications of hepatitis C infection. >>>> >>>> In short, the article did not suggest that the drug is a miracle cure, >>>> or even that it cures most patients or has decisively less and less >>>> important side effects than peg-interferon. >>>> >>>> However, as we discussed here, although there are lots of concerns >>>> about the prices in the US, almost no one questioned that the drug is >>>> extremely good. >>>> >>>> Recently there has been even more publicity about the drug, apparently >>>> based in part on new articles appearing in the New England Journal of >>>> Medicine. I took a quick look at the one article on previously untreated >>>> patients.(2) This concerned a combination of sofosbuvir and ledipasvir >>>> (also made by Gilead). Patients were randomized into 4 groups. However, >>>> all four groups received the combination of sofosbuvir and ledipasvir for >>>> 12 weeks. They differed only in whether they got an additional 12 weeks of >>>> the same combination, and in whether they did or did not also get >>>> ribavirin. Thus, I cannot see how the trial could have directly assessed >>>> the outcomes of treatment of sofosbuvir plus ledipsvir versus any >>>> alternative treatment (or even placebo). It seemed to be virtually a case >>>> series of patients treated with that drug. Because the appendix of the >>>> study also suggested that there were multiple inclusion and exclusion >>>> criteria, the apparently good results for sustained virologic response may >>>> simply have reflected a patient group with a very good prognosis. I have >>>> not yet had a chance to look at the adverse effect data (but it would be >>>> hard to interpret without a true control group.) Of course, there was no >>>> long-term follow-up and no assessment of clinical outcomes. >>>> >>>> So I am even more concerned that the hype about sofosbuvir and now >>>> other new antiviral treatments of hepatitis C is hardly based on clear >>>> evidence, and whether we are already heading for our next Tamiflu kind of >>>> case. >>>> >>>> Has anyone else had a chance to look over these or related trials and >>>> is willing to render an opinion? >>>> >>>> References. >>>> >>>> 1. Lawitz E et al. NEJM 2013. >>>> http://www.nejm.org/doi/full/10.1056/NEJMoa1214853 >>>> >>>> 2. Afdahl NA et al. NEJM 2014. >>>> http://www.nejm.org/doi/full/10.1056/NEJMoa1402454 >>>> >>>> >>>> -- >>>> >>>> <[log in to unmask]> >>>> >>>> >>> >> > > > -- > Roy M. Poses MD FACP > President > Foundation for Integrity and Responsibility in Medicine (FIRM) > [log in to unmask] > Clinical Associate Professor of Medicine > Alpert Medical School, Brown University > [log in to unmask] >