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Are dropout rates in trials higher than SOC?
Many people refer to the high dropouts from the Vertex trials. Having just completed the prove 3 trial, I have come to believe that trials are not for the faint of heart. There was a 25% chance of getting a placebo in Prove 3 and we are flying blind, since we can't see viral loads for 24 weeks!
My personal feeling is that if I knew that I was responding well and not on a placebo AND I had rescue drugs, I would be less likely to drop out.
Just curious about what other people think about the impact this would have on the end result.
Eric
My personal feeling is that if I knew that I was responding well and not on a placebo AND I had rescue drugs, I would be less likely to drop out.
Just curious about what other people think about the impact this would have on the end result.
Eric
Yes double blinded means that your doctor and you do not know what arm you are in. There are different levels of blinding and if test results are likely to top everyone off what arm you are in, they are often withheld. The prove 3 trial did not release any PCR results until 24 weeks. They resisted releasing at 24 weeks, since the trial had 48 week arms, but many people complained so loudly, that they finally agreed to release the data.
Viral loads with Telaprevir respond very differently than SOC, so a trial with previous non - responders would allow people to figure out what arm they were in, since they would see a radical difference if Telaprevir was in the mix. I think that might not be true for naive patients with no frame of reference.
Eric
Viral loads with Telaprevir respond very differently than SOC, so a trial with previous non - responders would allow people to figure out what arm they were in, since they would see a radical difference if Telaprevir was in the mix. I think that might not be true for naive patients with no frame of reference.
Eric
What my last comment was referring to with regards to my own stats is that I have less to lose by staying in the trial than someone else might and therefore, unless a health risk due to sides, would be more likely to stay in than someone who has more advanced liver damage. That's what I'm thinking and dunno if there's any credence to that.
Trish
Trish
Laurie: I think that if I hadn't seen at least a sizable drop in my viral load in the beginning I may have dropped out by now.I'm 10 weeks in.
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See now this brings up an interesting point. A trial is different things to different people.
I wondered how much response plays in a trial. I wondered how many people would drop out if they weren't doing well .. or as well as they wanted ... as they'd be less committed to finishing a trial than treatment, particularly when you don't know your dosage and you think you might do better with regular treatment.
Also, in Laurie's case, if you feel the trial drug is impacting you negatively and you're not responding as well as you'd like...there may be not much incentive to hang in there.
If you're later stages ... then perhaps even less because you don't want to use up one of your "nine lives" for what is now appearing to be a waste of a remainder of 30+ weeks when you could be taking more targeted treatment.
One of the reasons for me going into my trial was that I was Stage 1 damage. A throw of the dice means I might just get the trial drug .. and while I don't want to have to go through this more than once .. felt I could tolerate that if I had to for the chance at a kicka$$ drug that might knock this out of the park much better than SOC would.
So .. have been meaning to post that speculation on my part and Laurie's comment was a good segue into that.
Trish
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See now this brings up an interesting point. A trial is different things to different people.
I wondered how much response plays in a trial. I wondered how many people would drop out if they weren't doing well .. or as well as they wanted ... as they'd be less committed to finishing a trial than treatment, particularly when you don't know your dosage and you think you might do better with regular treatment.
Also, in Laurie's case, if you feel the trial drug is impacting you negatively and you're not responding as well as you'd like...there may be not much incentive to hang in there.
If you're later stages ... then perhaps even less because you don't want to use up one of your "nine lives" for what is now appearing to be a waste of a remainder of 30+ weeks when you could be taking more targeted treatment.
One of the reasons for me going into my trial was that I was Stage 1 damage. A throw of the dice means I might just get the trial drug .. and while I don't want to have to go through this more than once .. felt I could tolerate that if I had to for the chance at a kicka$$ drug that might knock this out of the park much better than SOC would.
So .. have been meaning to post that speculation on my part and Laurie's comment was a good segue into that.
Trish
We need to define what is meant by "blinded" and "double blind". As far as I'm aware, my trial is considered "double blind" because neither myself nor the researchers know what our dosages are until the trial is done.
We DO get our results as we go along, both viral load and CBC. Is it possible that getting your results along the way has nothing to do with being blinded? I can't imagine being in a trial that tells you NOTHING about how you're doing until you're done. That seems reckless. Can you explain further please? Thanks Eric.
Trish
We DO get our results as we go along, both viral load and CBC. Is it possible that getting your results along the way has nothing to do with being blinded? I can't imagine being in a trial that tells you NOTHING about how you're doing until you're done. That seems reckless. Can you explain further please? Thanks Eric.
Trish
I was in that trial last year...I was one of the lucky ones to get the placebo. The only positive thing was when I got dropped for non-response I was automatically eligible for the roll-over trial. So far I've been clear for 13 weeks, I went non-detect after the second week.
Are they relapsing because tx didn't work for them or because they dropped out before completeing tx?
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I meant that in blinded trials, dropouts would be random, so people with a great chance of SVR would be included in the dropout rate. In unblinded trials, people with EVR would be less likely to dropout and people with poor viral response would be more likely to dropout. This would be a positive influence on total SVR rates.
Eric
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I meant that in blinded trials, dropouts would be random, so people with a great chance of SVR would be included in the dropout rate. In unblinded trials, people with EVR would be less likely to dropout and people with poor viral response would be more likely to dropout. This would be a positive influence on total SVR rates.
Eric
You might be right.
I think that if I hadn't seen at least a sizable drop in my viral load in the beginning I may have dropped out by now.I'm 10 weeks in.
As it is I went undectable at week 2...so it causes me to stay in.
The trial is an aweful lot of drugs. Side effects are very ruff. Roche is allowing rescue drugs for me....but even those come with their own little sides.
If the trial wasn't working I don't think I'd be putting myself through all of this. I'd probably dropout and seek out reg. tx.
One thought though.....
"more people that are likely to relapse will dropout and less people that are likely to succeed will dropout. "
Are they relapsing because tx didn't work for them or because they dropped out before completeing tx?
Laurie
I think that if I hadn't seen at least a sizable drop in my viral load in the beginning I may have dropped out by now.I'm 10 weeks in.
As it is I went undectable at week 2...so it causes me to stay in.
The trial is an aweful lot of drugs. Side effects are very ruff. Roche is allowing rescue drugs for me....but even those come with their own little sides.
If the trial wasn't working I don't think I'd be putting myself through all of this. I'd probably dropout and seek out reg. tx.
One thought though.....
"more people that are likely to relapse will dropout and less people that are likely to succeed will dropout. "
Are they relapsing because tx didn't work for them or because they dropped out before completeing tx?
Laurie
gkucklich: good to see you posting again. How are you doing these days?
Like Trish, I never heard of any organ failures and that is not included in the Vertex paperwork to the best of my knowledge.
Trish: You make a good point about the dropouts caused by people being aware of not responding.
I think if you look at the impact of dropouts on SVR the results will be different if the PCR tests are revealed, but perhaps not when you just look at total dropouts: more people that are likely to relapse will dropout and less people that are likely to succeed will dropout. What do you think?
Eric
Like Trish, I never heard of any organ failures and that is not included in the Vertex paperwork to the best of my knowledge.
Trish: You make a good point about the dropouts caused by people being aware of not responding.
I think if you look at the impact of dropouts on SVR the results will be different if the PCR tests are revealed, but perhaps not when you just look at total dropouts: more people that are likely to relapse will dropout and less people that are likely to succeed will dropout. What do you think?
Eric
"I know some dropped out because one of their organs began to give out."
I've heard about the rash but not this. Do you have more information on this?
Trish
I've heard about the rash but not this. Do you have more information on this?
Trish
I keep a diary on my trial also .. from the time of the screening to the acceptance baseline tests and weekly tests, have been there weekly for 6 weeks - just had my first of 2 x 2 week appointments. All through the Canadian winter and all a 1- 2 hour drive away depending on traffic. I'm not complaining, it has not been a hardship. I'm motivated, I have never minded driving - quite enjoy it and they have made my appointments at 8am as many times as possible for me so I don't miss too much work. For someone else, with a longer drive and different work situation (my boss has even given me overtime to counter-act the time lost - no wonder I'm not changing jobs right now!) it might become too much, regardless of the benefits.
I agree with you .. that the PCR's are important. We are getting them all the way through. We're still considered double blind, in that neither us nor the researchers will know what arm we're in til we're done the protocol .. however, we do get our results each time we go, the CBC and the PCR. Our Australian friend in the same trial, Emi, wasn't going to get his until 24 weeks and when he found out we will get ours at each visit, advocated for himself and now he will get his every other week at least. Interesting.
Do you think PCR's can also work the other way? That people would drop out if they knew the results were not favourable? I knew what I was getting into and I already knew I would not .. but then I have some time on my side and I felt I could afford to make that kind of commitment.
Gluck: that is the only reason I would drop out .. if the side effects were too threatening for one reason or another.
Wonder if rescue drugs introduced as a last resort as in my trial would make a difference? Laurie had them and is still in the trial.
Interesting discussion, Eric. I too think it's important. Partly to understand the results better and to understand the risks to ourselves better.
Regards,
Trish
I agree with you .. that the PCR's are important. We are getting them all the way through. We're still considered double blind, in that neither us nor the researchers will know what arm we're in til we're done the protocol .. however, we do get our results each time we go, the CBC and the PCR. Our Australian friend in the same trial, Emi, wasn't going to get his until 24 weeks and when he found out we will get ours at each visit, advocated for himself and now he will get his every other week at least. Interesting.
Do you think PCR's can also work the other way? That people would drop out if they knew the results were not favourable? I knew what I was getting into and I already knew I would not .. but then I have some time on my side and I felt I could afford to make that kind of commitment.
Gluck: that is the only reason I would drop out .. if the side effects were too threatening for one reason or another.
Wonder if rescue drugs introduced as a last resort as in my trial would make a difference? Laurie had them and is still in the trial.
Interesting discussion, Eric. I too think it's important. Partly to understand the results better and to understand the risks to ourselves better.
Regards,
Trish
I know some dropped out because one of their organs began to give out. I think it is important to remember that tele is a drug with real side effects that can really hurt some folk.
I also remember somewhere getting the information that the trial Eric was in observed that non responders did not fair well with tele. Maybe arm C was sort of their control for this.
I also remember somewhere getting the information that the trial Eric was in observed that non responders did not fair well with tele. Maybe arm C was sort of their control for this.
Prove 3 is a phase 2 trial in FDA terms. It is the third trial of Telaprevir so I guess that is where the number came from.
My own experience with the Vertex trial is that it was very demanding. I had to keep a diary and had many visits to the medical center. The most difficult part of the trial for me was the lack of PCR results. If I had known that I became undetectable by week 2, it would have been much easier to take.
I do think that Prove 3 will have fewer dropouts than the rest of the trial, because the trial was made up of people that failed prior treatments. I think those of us in Prove 3 worked hard to get into the trial and were very motivated to stick with it.
I think that after some experience using the new drugs, the docs will be better able to treat the side effects and coach the patients how to better deal with them.
Thanks for doing some research. I think this is an important topic.
Take care,
Eric
My own experience with the Vertex trial is that it was very demanding. I had to keep a diary and had many visits to the medical center. The most difficult part of the trial for me was the lack of PCR results. If I had known that I became undetectable by week 2, it would have been much easier to take.
I do think that Prove 3 will have fewer dropouts than the rest of the trial, because the trial was made up of people that failed prior treatments. I think those of us in Prove 3 worked hard to get into the trial and were very motivated to stick with it.
I think that after some experience using the new drugs, the docs will be better able to treat the side effects and coach the patients how to better deal with them.
Thanks for doing some research. I think this is an important topic.
Take care,
Eric
Your initial post made me very curious but I really didn't have time to explore that curiosity until now. I finally spent a bit of time looking around. Here's what I found out.
Percentage of drop-out rate in regular SOC is around 5 - 9%. Now.. I need to research that a bit MORE to conclusively settle on that number. That is one of the figures quoted in a comparison between regular SOC dropout rates and the trial in question, which was SOC for those with end stage renal disease and HCV.
In general however .. reasons for drop-out rates in clinical trials included:
* Location - the further away from the trial centre, the greater the chance of drop-out due to non-compliance
*Depression - considered a major reason for drop-out in both clinical trials and SOC - I know my trial was very stringent on depression and now I begin to see why. I imagine they all are, yes?
*Intolerable side effects
Telaprevir trial drop-out rates in a couple of the articles were noted as 9% in Phase I and 12.5% in Phase II apparently. I don't know about Phase III/ Prove 3? I do get confused as to the difference between Prove 3 and Phase III - could you enlighten me please?
So .. with such scant data as I've provided, it seems that clinical trials have a few extra reasons for drop-out. Distance, more sensitivity to depression, intolerable side effects when you take into account that there are no rescue drugs or a great reluctance to use rescue drugs until absolutely necessary.
With that in mind, the drop-out rates for Telaprevir don't seem that out of line.. IF my numbers are right.
And Laurie was right .. our R1626 trial does allow rescue drugs but they'd rather do just about anything else first. So it's not NO rescue drugs in our trial but certainly they won't be coming easy and unless absolutely necessary. Dosage reductions will come first.
I know this comes very late ... but it's been simmering on my "really want to do" list and it finally came up. Hope it's not totally redundant by now. :)
Take care.
Trish
Percentage of drop-out rate in regular SOC is around 5 - 9%. Now.. I need to research that a bit MORE to conclusively settle on that number. That is one of the figures quoted in a comparison between regular SOC dropout rates and the trial in question, which was SOC for those with end stage renal disease and HCV.
In general however .. reasons for drop-out rates in clinical trials included:
* Location - the further away from the trial centre, the greater the chance of drop-out due to non-compliance
*Depression - considered a major reason for drop-out in both clinical trials and SOC - I know my trial was very stringent on depression and now I begin to see why. I imagine they all are, yes?
*Intolerable side effects
Telaprevir trial drop-out rates in a couple of the articles were noted as 9% in Phase I and 12.5% in Phase II apparently. I don't know about Phase III/ Prove 3? I do get confused as to the difference between Prove 3 and Phase III - could you enlighten me please?
So .. with such scant data as I've provided, it seems that clinical trials have a few extra reasons for drop-out. Distance, more sensitivity to depression, intolerable side effects when you take into account that there are no rescue drugs or a great reluctance to use rescue drugs until absolutely necessary.
With that in mind, the drop-out rates for Telaprevir don't seem that out of line.. IF my numbers are right.
And Laurie was right .. our R1626 trial does allow rescue drugs but they'd rather do just about anything else first. So it's not NO rescue drugs in our trial but certainly they won't be coming easy and unless absolutely necessary. Dosage reductions will come first.
I know this comes very late ... but it's been simmering on my "really want to do" list and it finally came up. Hope it's not totally redundant by now. :)
Take care.
Trish
There is no question about the handpicking of patients...when I last saw my doc, I asked about a Telaprevir trial going on at his hospital, the University of Washington. He was kind but pretty direct when he explained to me that while the trial might say "to include non-responders", the trial directors were NOT going to pick many non-responders and that my particular "profile"...viral breakthru at 30 weeks would just about guarantee that they would NOT pick me.
So there is a heck of a lot of "cherry-picking" going on, but considering the cost of the trials and the difficulty of getting a drug approved...Vertex can cherry pick all they want! The ultimate goal is to get the drug approved and available to all of us.
How could anyone insure a fair, representative sample of patients anyway? There is a whole world of unique folks out here? What's important is the approval of the drug.
Willow
So there is a heck of a lot of "cherry-picking" going on, but considering the cost of the trials and the difficulty of getting a drug approved...Vertex can cherry pick all they want! The ultimate goal is to get the drug approved and available to all of us.
How could anyone insure a fair, representative sample of patients anyway? There is a whole world of unique folks out here? What's important is the approval of the drug.
Willow
If I had any complaint about the trial it would be that I thought that they should have allowed the group C (no Riba group) the ability to have 'rollover'. Our group was gypted in my opinion. Hardly any of us that didn't get all 3 drugs, cleared the virus (in the non-responders/relapsers trial.) I feel that they should come back and say, 'we've modified the protocol and we're going to offer you group C people the ability to have all 3 drugs now'. But, on the flip-side, I did know that going in, and I still signed up for it, so; it's not like I didn't know what I was getting into.
I'm in a trial for RO04588161, Phase II.
When this trial started they said no rescue drugs allowed, but when my blood counts crashed a couple of weeks ago they desided to allow me Procrit and Nuepogen. So in this trial Roche is allowing rescue drugs.
Thank God because I would have had no choice but to drop out.
When this trial started they said no rescue drugs allowed, but when my blood counts crashed a couple of weeks ago they desided to allow me Procrit and Nuepogen. So in this trial Roche is allowing rescue drugs.
Thank God because I would have had no choice but to drop out.
The trials I've seen with one arm seem to be the early Phase I trials that start out to see what the side effects of the drug are before it's moved further along into the trial process. My trial is a Phase II, double blind, 7 arms. However, certainly that doesn't mean they're all like that but it seems typical of a Phase II and then less arms in a Phase II.
In some ways, in a double blind trial and with these drugs, it's hard to "hand pick" I think....but the screening process itself does eliminate certain things by necessity. Those who've ever had a history of various health situations aren't getting in. That makes sense to me too. There are no rescue drugs, so you don't want extra health complications thrown in to deal with when you don't have the tools to apply to them. Also, the data is more pure. You're getting "baseline" results, so to speak. Beyond that, when the arms are multi and double-blinded, it's all left to the pick of the draw.
Trish
In some ways, in a double blind trial and with these drugs, it's hard to "hand pick" I think....but the screening process itself does eliminate certain things by necessity. Those who've ever had a history of various health situations aren't getting in. That makes sense to me too. There are no rescue drugs, so you don't want extra health complications thrown in to deal with when you don't have the tools to apply to them. Also, the data is more pure. You're getting "baseline" results, so to speak. Beyond that, when the arms are multi and double-blinded, it's all left to the pick of the draw.
Trish
Right you are! Vitorin and Zetia were the ones I was thinking about. I am so brain-dead these days I can't remember my own name somethimes (I should have shortened it).
I am glad I made sense to you, but I am not sure how that reflects on your judgement ;)
Igottagonow! Sleep bekons.
Best to you,
Brent
I am glad I made sense to you, but I am not sure how that reflects on your judgement ;)
Igottagonow! Sleep bekons.
Best to you,
Brent
I think you are right and I definitely haven't read about the bias in trials. I am sure the pharm companies would like to influence them any way they can. Refer to the delayed release of results from the test of the non-statin anti cholesterol drugs recently (I forget their names despite the costant bombardment of TV ads! :). Deliberate mischief in the study formulation is hard to counter.
A study with only one arm is hard to draw tight conclusions from. That is why the double blind ones with multiple arms are of the greatest scientific benefit. If the entire cohort is on one TX arm, then there is no comparison unless other studies and TXs had the same qualifications on their cohort.
Also, there is what Scotty says: "I KNEW I was being treated by the symtoms and 'other methods' "
It is hard to quantify what the result of motivation and attitude are on disease. I am a believer that it helps whether there is scientific evidence to back it up or not. I am a little soft, here.
I am not sure the study design can eliminate all forms of bias. Maybe the best we can do is identify the potential sources of bias, like you have pointed out.
Brent
A study with only one arm is hard to draw tight conclusions from. That is why the double blind ones with multiple arms are of the greatest scientific benefit. If the entire cohort is on one TX arm, then there is no comparison unless other studies and TXs had the same qualifications on their cohort.
Also, there is what Scotty says: "I KNEW I was being treated by the symtoms and 'other methods' "
It is hard to quantify what the result of motivation and attitude are on disease. I am a believer that it helps whether there is scientific evidence to back it up or not. I am a little soft, here.
I am not sure the study design can eliminate all forms of bias. Maybe the best we can do is identify the potential sources of bias, like you have pointed out.
Brent
Eric,
I felt lucky to get in the study to begin with however if I thought in my heart that I wasn't getting the 'real thing' then I don't think I could have made it. There are several queues to know what is going on and some are even encouraged to go to independent sources to verify the efficacy of the drugs they are taking.
So I think it's about the same drop out rate to the degree that one doesn't know if they are truly being treated or not. I KNEW I was being treated by the symtoms and 'other methods' to know so that gave me great motivation to continue. As well as you and others that were open with their struggles and hung in there.
Warmly (4 weeks to go)
Scotty
I felt lucky to get in the study to begin with however if I thought in my heart that I wasn't getting the 'real thing' then I don't think I could have made it. There are several queues to know what is going on and some are even encouraged to go to independent sources to verify the efficacy of the drugs they are taking.
So I think it's about the same drop out rate to the degree that one doesn't know if they are truly being treated or not. I KNEW I was being treated by the symtoms and 'other methods' to know so that gave me great motivation to continue. As well as you and others that were open with their struggles and hung in there.
Warmly (4 weeks to go)
Scotty
About the "hand picking":
I am thinking that the picking of the participants would not affect the outcome. If it did, then the study would be of much less value.
In a trial situation, they handpick the cohort of people they will use in the trial and the parameters for acceptance (sex, age, disease characteristics, previous treatments, etc.) depending on what they are trying to prove or disprove. They will assign the patients at random from the cohort to different treatment arms (different TX vs. placebo or SOC). This is done at random so that, if the sample size is large enough, they can compare the rates of SVR, etc. between the treatment arms. There would be no "handpicking of which patients go to different arms of the study. Any biases in the picking of the cohort would apply to all TX arms of the study.
I am thinking that the picking of the participants would not affect the outcome. If it did, then the study would be of much less value.
In a trial situation, they handpick the cohort of people they will use in the trial and the parameters for acceptance (sex, age, disease characteristics, previous treatments, etc.) depending on what they are trying to prove or disprove. They will assign the patients at random from the cohort to different treatment arms (different TX vs. placebo or SOC). This is done at random so that, if the sample size is large enough, they can compare the rates of SVR, etc. between the treatment arms. There would be no "handpicking of which patients go to different arms of the study. Any biases in the picking of the cohort would apply to all TX arms of the study.
The trial was double blind, so even the researchers did not know what was happening. So all of us know nothing for 24 weeks. We did get the standard blood including liver panels. So, I know that my liver tests normalized within a week. I didn't even know if I was going to stop at 24 weeks or continue for a total of 48 weeks.
By the way, the more I read about the trial you are in, the more it looks very promising. Perhaps the next trial will include both drugs.
Eric
By the way, the more I read about the trial you are in, the more it looks very promising. Perhaps the next trial will include both drugs.
Eric
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