Monday, 22 June 2015

pharma win when they pick low hanging fruit

Flacco ME, Manzoli L, Boccia S, Capasso L, Aleksovska K, Rosso A, Scaioli G, De Vito C, Siliquini R, Villari P, Ioannidis JP.
Head-to-head randomized trials are mostly industry sponsored and almost always favour the industry sponsor.J Clin Epidemiol. 2015;68(7):811-820.
OBJECTIVES:To map the current status of head-to-head comparative randomized evidence and to assess whether funding may impact on trial design and results.
STUDY DESIGN AND SETTING: From a 50% random sample of the randomized controlled trials (RCTs) published in journals indexed in PubMed during 2011, we selected the trials with ≥100 participants, evaluating the efficacy and safety of drugs, biologics, and medical devices through a head-to-head comparison.
RESULTS: We analyzed 319 trials. Overall, 238,386 of the 289,718 randomized subjects (82.3%) were included in the 182 trials funded by companies. Of the 182 industry-sponsored trials, only 23 had two industry sponsors and only three involved truly antagonistic comparisons. Industry-sponsored trials were larger, more commonly registered, used more frequently noninferiority/equivalence designs, 
had higher citation impact, and were more likely to have "favorable" results (superiority or noninferiority/equivalence for the experimental treatment) than non industry-sponsored trials. Industry funding [odds ratio (OR) 2.8; 95% confidence interval (CI): 1.6, 4.7] and noninferiority/equivalence designs (OR 3.2; 95% CI: 1.5, 6.6), but not sample size, were strongly associated with "favorable" findings. Fifty-five of the 57 (96.5%) industry-funded noninferiority/equivalence trials got desirable "favorable" results.
CONCLUSION: The literature of head-to-head RCTs is dominated by the industry. Industry-sponsored comparative assessments systematically yield favorable results for the sponsors, even more so when non inferiority designs are involved.

You say which drug is best and I say I don't know. You need to do a head to head study and see which is the best or a non-inferiority study to show it is no worse. However in the published trials the pharma drugs always succeed. Go figure. This is because when pharma do head to heads they target the low hanging fruit so they can put their marketing departments on the job. Now if they put their drugs against generic cladribine would this change the status

14 comments:

  1. Show me a peer reviewed trial of Cladribine that is more effective that Alemtuzumab or Natalizumab. Then you have an argument.

    Why do you need to do a head to head study, this is what I find so frustrating, you all admit that MS is such an unpredictable disease and that everyone has varied disease course. So if you have phase 3 results of Cladribine and phase 3 results of say alemtuzumab, why then do you need to do another trial to put them in direct competition?? Surely the two results when you compare then answer that question? (assuming you were comparing the same disease type (RRMS/SPMS/PPMS etc) Are you expecting that your trials will product different results then the other phase 3 results?

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    1. Giovannoni et al 2010 and NEDA at 2years about 50% which is as good as alemtuzmab and natalizumab but 50% secondary autoimmunity verses nil and 1 in 95 chance of PML and that is not bad. Like wise £1500 verses £40,000 or£60,000 is not bad and as for the rest there is not much of a contest.

      However you miss the point because the comparitor is usually beta ├Čnterferon so the comparator wins except laquinimod which is a failure. If new drugs were made to go head to hesd against best option many will fail and so you have the current drugs forever.

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    2. I have heard of neuros wanting to do head to heads but as you say we know what the results will be and all you are doing is marketing as it is a case of mine is better than yours....companies should be paying for this.

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    3. Head to heads who are going to do this as company doing head to head with alemtuzumab would have to buy the alemtuzumab so a few hundred people times 60,000 pounds so multi million pound trial.

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    4. I think you miss a point as well. I have MS, I don't want the option of more drugs that are not as effective as the drugs that are out there. I want BETTER drugs. I get that you need to have variety in treatment options but globally we have around 12 different drugs. If I fail alemtuzumab, I have no option but to go on a trail proven less effective drug. (or pay for something like HSCT abroad) If Ocrelizumab is better than interferon but not as good as Alem, than all it means is more inferior choice. if Orcel is similar in results to Alem but less patient risk then it is a good option

      Pharma and a numbr of scientists/neuros are not focused on the number 1, the patient. You constantly bring up of a Cladribine but it has been dead for a number of years. You either need to spend loads of your time/effort convicing MERCK to bring the drug back, or swallow the failure and continue to work on BETTER optons for the patients.

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    5. Not only better options but above all SAFER options -

      I don't care for drugs which are potentially lethal -

      as I always say to my neuro: "I am not willing to die in order to ameliorate my MS, thank you very much"

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    6. How are you going to get better drugs?....Show they are better in terms of efficacy or better in terms of side-effects?

      How do you show a drug is better or safer.. you do a trial....How o you do this trial?

      In an age when you have 12 different drugs, the question one asks, Is it ethical to do placebo controlled trials any more. The answer should really be no but pharma are still doing this.

      So to get a better drug you should have to trial against an active, so at least everyone is being treated. Which comparator one do you choose?. Pharma will choose what they know they can beat.

      To do a superiority trial over something like natalizumab or Alemtuzumab is going to be very big to find a better therapeutic effect, but unless this is antigen specific the chances of worse side effects are enhanced.

      Now you your point. If ocreluzimab is better than interferon but not as good as alemtuzumab...in what sense...is as good....efficacy verses side effect?.

      Ocreluzimab and Alem probably have worse side effects than beta but are less efficacious.

      I predict ocreluzimab will be in the same order of efficacy as alemtuzumab but can have lower side effect, but how is it going to be used as an induction therapy or as a repeated therapy and then the issue to PML will arise..

      As to how I spend my time and my focus...maybe I should look after No. 1

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    7. On a related note, the regulator should classify patient selection. If you look at the trials for HSCT and those for Lemtrada, in Lemtrada you've got patients with early active disease and very low EDSS who are treatment naive (not failed any previous therapies), and HSCT recruiting patients with aggressive disease, requisite of failing two previous therapies, and EDSS up to 6.5, any disease duration, and even transitioning SPMS patients.

      We'll then see docs and commentators forget all about that, and compare the NEDA rates like for like.

      Which is ludicrous in my opinion.

      Why does the regulator not standardise the criteria - even if they use a couple of subsets. And then use natural history/older placebo trial data as the control arm.

      Re-running a placebo control arm for each study is just repeating the same experiment over and over again, to the detriment of patients' health.

      No other field works on this crazy basis. If you want to prove a new car is faster than the land speed record, you meet the base parameters to make it fair with previous conditions, then test the new car. Nobody says it's invalid unless you beat the old record holder in a head to head race.

      I can't think of another field where the new "best" has to directly beat the "old best" in a head-to-head. It's always the same; standardise the baseline parameters, get an independent judge and try to beat the recorded output of the current record holder (in its absence).

      Why is the medical establishment stuck in the 1800s?

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    8. P.S. We already have found ways that are BETTER and SAFER in animals...problem is there is no patent and the technology is no longer available or not sufficiently developed and we would need to start and finance another company to develop the approach for humans.

      "A number of scientists/neuros are not focused on the number 1"....Who are you referring to...

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    9. Good point re hsct those doing it are generally third line verses first line for others. In cancer you have survival which is pretty hard edged. In MS you have relapse rate and the relapse rate for beta interferon trial is as bad as the placebo arm in current
      arm.

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  2. if cladribine is comparator then there will be more cancers in the patients taking it.

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    1. Actually there are no more cancers in cladribine than in another other DMT based on results from pivotal trials. What was unusual in the CLARITY trial was that there were no cancers in the placebo arm. This was not the case in the ORACLE trial.

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    2. that's not really a valid argument- the whole point of an rct is that it has it's own internal control. comparing with another trial needs adjustment for other factors, it cannot be just eyeballed.

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    3. So you dont believe in chance... however you are right this needs some sophisticated stats you can comment when the paper is published

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