3 ms·

The problem is the marketing department. Most of the big diseases (cancer, depression, heart disease, dementia, etc) have complex and diverse causes and so only

The problem is the marketing department. Most of the big diseases (cancer, depression, heart disease, dementia, etc) have complex and diverse causes and so only a subset of patients will respond to any one drug. At Phase 2 the trial co-ordinators have relatively strict inclusion criteria targeting the likely responders (i.e. the subset that have the version of the disease the drug will work on). When it gets to Phase 3 marketing gets involved in the inclusion criteria and they want the criteria to be as broad as possible so they can market to the widest number of patients. The aim is to have a criteria that is as broad as possible where the Phase 3 trial just scrapes across the line. This is a difficult thing to get right and sometime they include too many non-responders and the trial falls over. The only real solution is to get the cost of developing a drug down so that there is not the need to go so broad. Of course this will require taking more risks (the level of pre-clinical and clinical testing needs to be reduced) so I am not sure this is viable.

smallnamespace 8y ago
You sound like you understand this process well, so dumb question: why is the Phase 3 process so rigid? Wouldn't it make more sense to simply have multiple inclusion criteria, (e.g. broad, more targeted, and same as Phase 2) and collect enough data in the front to be able to discriminate the patient at an individual level? That way if Phase 3 for 'broad' criteria fail, you can still demonstrate the drug works for a more strict population and maybe actually release it with that on the label? This also avoids data mining (where you keep looking for subsets until one seems to pass your significance criterion) since you came up with the criteria ahead of time.
- danieltillett 8y ago
  The reason why is that you can’t make any money just selling to the sub-population in many cases. Yes you are right that you can design the trial to identify the sub-population that the drug works in. Sometimes drug companies do do this, but if they are going to go down this path they normally run a tighter Phase 3 trial and then try to expand post-approval by running more trials. It is all a cost/benefit analysis taking into account the patent life and lots of other commercial factors. The point I was making is that a high failure rate at Phase 3 is to be expected given the marketing needs of the company. A Phase 3 trial is not just a scientific exercise in proving a drug works, it is a complex balancing act where commercial concerns are critical.
- lekanwang 8y ago
  You'll need more patients, which is expensive. But yes, you're actually right -- sponsors do run stratified phase 3 trials where subsets of patients are measured independently per pre-approved statistical analysis plan. The rub is that your patient population and your trial design needs to be sufficiently statistically powered to do that kind of analysis. The required number of patients quickly increases for the number of stratifications/subsets you're trying to prove an indication for, and patients are extremely expensive, so sponsors generally try to run the smallest trial possible while still being adequately statistically powered. This is generally why in Phase IIs, sponsors will stratify by exploratory biomarkers, where there may not be sufficient statistical power per stratification, but can give them some idea for what to include in the IIIs.
refurb 8y ago
As someone who works in the industry, none of this seems accurate. - Marketing gets involved before phase 3. Phase 2 results are usually where the business decision to proceed to phase 3 are made, so commercial needs input on the trial design. - Inclusion/exclusion criteria might be tweaked between phase 2 and 3, but they don't tend to drastically change as you're just asking for the trial to fail. - Development works with the FDA to craft inclusion criteria that preserves the scientific rigor of the trials, but also allows for the broadest possible indication. In general, the FDA grants a much broader label than what is described in the trial criteria.
- danieltillett 8y ago
  You have basically just summarised what I said :) I would not say the criteria are just “tweaked” between Phase 2 and 3 with any drug aimed at a broad market. It is always a balance between broadness and success and sometimes even the best in the business get it wrong. The FDA do allow a broader label than the exact trial criteria, but not massively so. If you restrict the Phase 3 to an identifiable sub-population good luck getting approval to expand to the larger population without running post-approval trials.
  - refurb 8y ago
    Where we disagree is on three points:(1) marketing gets involved well before phase 3,(2) most trial criteria don’t change that much between phase 2 and 3 [yes there are exceptions] and (3) the FDA allowing a broader label than inclusion criteria. As for the last one, most phase 3 trials have strict criteria: no other diseases, age limits, disease severity limits, etc. Those typically don’t make it into the label’s indication. I do agree that trials are designed to balance getting a positive outcome vs. the broadest population possible, but marketing isn’t the only one driving that.
    - danieltillett 8y ago
      1. Yes marketing gets involved before Phase 3, but they tend to not have the clout they have going into Phase 3 - generally when it is unclear that you have something that works at all it hard for marketing to argue in favour of broadening the inclusions criteria. 2. I think your point 2 is where we disagree the most. We are really arguing over what is a significant change or not. 3. The FDA will be looser on some things like age and other diseases (within reason as you won’t get approval for children if you only trial in adults), but not on sub-groups. If you make your trial exclude on some disease sub-group criteria you are not going to get FDA approval to go outside that sub-group and sell to everyone with the disease. Who is driving trial broadening other than marketing? If I want the drug to succeed I want the trial population to be a homogeneous as possible and only include likely responders.
Gatsky 8y ago
This isn't quite right - the selection of patients is usually not explicitly looser in phase 3 trials. Speaking from experience in oncology, in early phase trials, the patients are younger, healthier, wealthier, better educated, have less burden of disease and also probably have better disease biology. This is partly because doctors have to decide to refer a patient for a trial, which may be at another hospital or even another city - they select the 'best' patients for these purposes. This is just being practical in many ways - an 80 year old in a wheel chair isn't going to be able to spend 2 hours commuting every day to enrol in a phase I trial. A single mother with 4 kids working 3 jobs is also going to struggle to take multiple days off work for the trial. Patients that self-select for early phase trials are also a distinct group, generally healthier, wealthier and better educated. There is a subtle point about disease biology - many early phase trials start in populations that have run out of other treatment options. You actually need a relatively indolent cancer to make it to this stage. Very aggressive tumours will kill the patient before they can get through 1 or max 2 lines of therapy to even be eligible for the trial. In phase 3 trials, these selection biases are less prevalent (that's the point) and randomisation also takes out the effect of patients that were going to do relatively well anyway receiving a treatment that may not be effective.

smallnamespace 8y ago

You sound like you understand this process well, so dumb question: why is the Phase 3 process so rigid? Wouldn't it make more sense to simply have multiple inclusion criteria, (e.g. broad, more targeted, and same as Phase 2) and collect enough data in the front to be able to discriminate the patient at an individual level? That way if Phase 3 for 'broad' criteria fail, you can still demonstrate the drug works for a more strict population and maybe actually release it with that on the label? This also avoids data mining (where you keep looking for subsets until one seems to pass your significance criterion) since you came up with the criteria ahead of time.

danieltillett 8y ago
The reason why is that you can’t make any money just selling to the sub-population in many cases. Yes you are right that you can design the trial to identify the sub-population that the drug works in. Sometimes drug companies do do this, but if they are going to go down this path they normally run a tighter Phase 3 trial and then try to expand post-approval by running more trials. It is all a cost/benefit analysis taking into account the patent life and lots of other commercial factors. The point I was making is that a high failure rate at Phase 3 is to be expected given the marketing needs of the company. A Phase 3 trial is not just a scientific exercise in proving a drug works, it is a complex balancing act where commercial concerns are critical.
lekanwang 8y ago
You'll need more patients, which is expensive. But yes, you're actually right -- sponsors do run stratified phase 3 trials where subsets of patients are measured independently per pre-approved statistical analysis plan. The rub is that your patient population and your trial design needs to be sufficiently statistically powered to do that kind of analysis. The required number of patients quickly increases for the number of stratifications/subsets you're trying to prove an indication for, and patients are extremely expensive, so sponsors generally try to run the smallest trial possible while still being adequately statistically powered. This is generally why in Phase IIs, sponsors will stratify by exploratory biomarkers, where there may not be sufficient statistical power per stratification, but can give them some idea for what to include in the IIIs.

refurb 8y ago

As someone who works in the industry, none of this seems accurate. - Marketing gets involved before phase 3. Phase 2 results are usually where the business decision to proceed to phase 3 are made, so commercial needs input on the trial design. - Inclusion/exclusion criteria might be tweaked between phase 2 and 3, but they don't tend to drastically change as you're just asking for the trial to fail. - Development works with the FDA to craft inclusion criteria that preserves the scientific rigor of the trials, but also allows for the broadest possible indication. In general, the FDA grants a much broader label than what is described in the trial criteria.

danieltillett 8y ago
You have basically just summarised what I said :) I would not say the criteria are just “tweaked” between Phase 2 and 3 with any drug aimed at a broad market. It is always a balance between broadness and success and sometimes even the best in the business get it wrong. The FDA do allow a broader label than the exact trial criteria, but not massively so. If you restrict the Phase 3 to an identifiable sub-population good luck getting approval to expand to the larger population without running post-approval trials.
- refurb 8y ago
  Where we disagree is on three points:(1) marketing gets involved well before phase 3,(2) most trial criteria don’t change that much between phase 2 and 3 [yes there are exceptions] and (3) the FDA allowing a broader label than inclusion criteria. As for the last one, most phase 3 trials have strict criteria: no other diseases, age limits, disease severity limits, etc. Those typically don’t make it into the label’s indication. I do agree that trials are designed to balance getting a positive outcome vs. the broadest population possible, but marketing isn’t the only one driving that.
  - danieltillett 8y ago
    1. Yes marketing gets involved before Phase 3, but they tend to not have the clout they have going into Phase 3 - generally when it is unclear that you have something that works at all it hard for marketing to argue in favour of broadening the inclusions criteria. 2. I think your point 2 is where we disagree the most. We are really arguing over what is a significant change or not. 3. The FDA will be looser on some things like age and other diseases (within reason as you won’t get approval for children if you only trial in adults), but not on sub-groups. If you make your trial exclude on some disease sub-group criteria you are not going to get FDA approval to go outside that sub-group and sell to everyone with the disease. Who is driving trial broadening other than marketing? If I want the drug to succeed I want the trial population to be a homogeneous as possible and only include likely responders.

Gatsky 8y ago

This isn't quite right - the selection of patients is usually not explicitly looser in phase 3 trials. Speaking from experience in oncology, in early phase trials, the patients are younger, healthier, wealthier, better educated, have less burden of disease and also probably have better disease biology. This is partly because doctors have to decide to refer a patient for a trial, which may be at another hospital or even another city - they select the 'best' patients for these purposes. This is just being practical in many ways - an 80 year old in a wheel chair isn't going to be able to spend 2 hours commuting every day to enrol in a phase I trial. A single mother with 4 kids working 3 jobs is also going to struggle to take multiple days off work for the trial. Patients that self-select for early phase trials are also a distinct group, generally healthier, wealthier and better educated. There is a subtle point about disease biology - many early phase trials start in populations that have run out of other treatment options. You actually need a relatively indolent cancer to make it to this stage. Very aggressive tumours will kill the patient before they can get through 1 or max 2 lines of therapy to even be eligible for the trial. In phase 3 trials, these selection biases are less prevalent (that's the point) and randomisation also takes out the effect of patients that were going to do relatively well anyway receiving a treatment that may not be effective.