6 ms·

It seems like the key to making medical progress is realizing that not all treatments are "one size fits all" and figuring out why treatments that are safe and

It seems like the key to making medical progress is realizing that not all treatments are "one size fits all" and figuring out why treatments that are safe and effective for some people are unsafe for others. The vaccine from this story seemed to be safe and effective for some participants, but nearly killed another. How can we differentiate the people that it will help from the people that it could kill? This is a real problem in FDA approved medications. Just look at the side effects list for some of the "biologic" TNF blocking treatments for autoimmune diseases. Yet they are beneficial for most people.

djsumdog 9y ago
Human bodies are vastly different and one of the biggest difficulties is finding compounds that work the same 99% of the time, with minimal but known and treatable side effects. There's a reason this research takes so long. Things might have gotten to market sooner decades ago, but it all comes down to a trade-off with potential good vs safety. When political maneuvering gets in the way, you can get things like the Vioxx disaster. Even with Vioxx, FDA monitoring and procedures did do what they were suppose to in identifying the problem and pulling it off the market. The biggest problem really seems to be money, resources and funding the research. You might discover something promising, but your company will need to pay all those people, buy equipment and purchase animals to go forward. If you get to monkeys and lose a single one, you gotta go back to the beginning. You might find a side effect in 5% that's really bad/serious and your entire compound might need to be scrapped. Companies need to make money off of those investments so the compounds that do succeeded might become insanely expensive. The entire process is pretty backwards and I know people who are biochemists in this field who get paid really shitty despite their important work. A lot of money goes to equipment, but a lot also goes to management and cronies in the shops that can fund this stuff. It's a mess. There needs to be a better, not-for-profit model where a failed compound doesn't matter as much.
- barry-cotter 9y ago
  > There's a reason this research takes so long. Things might have gotten to market sooner decades ago, but it all comes down to a trade-off with potential good vs safety. Agreed. We’re way past the sane point on the trade off. Aspirin would not pass FDA review under the current regime. Efficacy testing doesn’t appear to do much good but it clearly makes getting a drug to market slower and more costly. For more on this see http://www.fdareview.org/ http://www.fdareview.org/
  - HarryHirsch 9y ago
    Efficacy testing doesn’t appear to do much good Come again, it's not important that any medication performs as advertised?! The purpose of Phase II testing is to determine if the new compound is better than placebo; the success rate is ~ 30 %, 70 % are no better than placebo. 70 % of candidates are as good as taking nothing at all. In a public health system this is the most important question to be answered: does the new treatment offer a greater benefit to patients - if not you can't ask the public purse to pay for it. I can also see the risk of backlash - the public perception of bigpharma is already low; if it begins to offer expensive treatments of low value trust in the institutions will erode further.
  - arkades 9y ago
    > aspirin wouldn’t pass We have a number of drugs in the same class that are as or more effective with less frequent adverse effects, and the same price to market. It is also one of the leading causes of toxic ODs presenting to the ED. Aspirin shouldn’t pass as an over the counter Anywhere, and wouldn’t but for historical inertia. Don’t confuse familiarity with safety. > efficacy testing doesn’t appear to do much good Efficacy testing is literally how we determine whether a drug works, and what the magnitude of its effects are. Without it, we’d have no idea if a drug worked, if it worked better or worse than competitor drugs, if it worked better or worse for some conditions or sub populations, etc. It’s -the- key information generating step on drugs. This comment is ridiculous to the point of caricature. >fdareview A site from the far-right, unknown-anywhere-but-Fox-news Independent Institute. Can you guess before popping the link open whether they advocate on lightening regulatory burdens on pharma companies?
    - opo 9y ago
      >> aspirin wouldn’t pass >We have a number of drugs in the same class that are as or more effective with less frequent adverse effects, and the same price to market. It is also one of the leading causes of toxic ODs presenting to the ED. Aspirin shouldn’t pass as an over the counter Anywhere, and wouldn’t but for historical inertia. Don’t confuse familiarity with safety. Could you add some more data to back up your statements? For example, you state "It is also one of the leading causes of toxic ODs presenting to the ED" >...During the latter part of the 20th century, the number of poisonings from salicylates declined, mainly because of the increased popularity of other over-the-counter analgesics such as paracetamol (acetaminophen). Fifty-two deaths involving single-ingredient aspirin were reported in the United States in 2000; however, in all but three of these cases, the reason for the ingestion of lethal doses was intentional—predominantly suicidal. https://en.wikipedia.org/wiki/Salicylate_poisoning https://en.wikipedia.org/wiki/Salicylate_poisoning Considering that literally thousands of tons of aspirin are consumed every year, this safety record likely compares well with other drugs. As a comparison, the most commonly used alternative to aspirin is acetaminophen and that is certainly much more dangerous: >...Many over-the-counter and prescription-only medications contain paracetamol. Because of its wide availability paired with comparably high toxicity, (compared to ibuprofen and aspirin) there is a much higher potential for overdose.[88] Paracetamol toxicity is one of the most common causes of poisoning worldwide.[22] In the United States, the United Kingdom, Australia, and New Zealand, paracetamol is the most common cause of drug overdoses.[17][89][90] Additionally, in both the United States and the United Kingdom it is the most common cause of acute liver failure.[91][7] https://en.wikipedia.org/wiki/Paracetamol_poisoning https://en.wikipedia.org/wiki/Paracetamol_poisoning >...A site from the far-right, unknown-anywhere-but-Fox-news I agree with you that efficacy testing of potential new drugs is important, but adding a statement with pejorative labelling like this feels somewhat like you are simply trying to poison the well.
- HarryHirsch 9y ago
  There needs to be a better, not-for-profit model where a failed compound doesn't matter as much Phase II/III clinical testing is expensive, and the failure rate (i.e. low efficacy, compound simply doesn't perform as expected, and certainly no better than what's already at market) is high. That's what it is, there isn't much that can be done at that front. Thankfully a few months ago Goldman Sachs directly addressed the elephant in the room: pharma yields bad returns, investment in pharma is inadvisable. There needs to be a different financing model, perhaps from the public purse.
  - refurb 9y ago
    There needs to be a different financing model, perhaps from the public purse. How does that solve the issue at hand? As you said, development is expensive and has a high failure rate. Why would public funding change either one of those?
    - HarryHirsch 9y ago
      New antibiotics are high on the list of things that are needed, but they will only be used as treatment of last resort, this is where the traditional investment model fails. Development is too expensive to ever recover the outlays. Right now science can't do anything about the high failure rates in Phase II and Phase III trials. The problem isn't to come up with a compound against your target of choice, it's that apart from clinical trials we don't have a way to predict if in real life it will perform better than placebo (Phase II) or adequately (Phase III).
      - Fomite 9y ago
        While commonly used as an example, I'll note this isn't actually even always true for antibiotics. The development of Fidaxomicin/Difficid is actually an example of a fairly inexpensive clinical trial (by clinical trial standards), and Merck didn't buy Cubist for $9.5 billion for a drug they don't think will recover their outlay.
    - tikhonj 9y ago
      At the very least it would spread the cost out over everyone rather than just the people who end up needing the drugs that pass the expensive process.
- cryoshon 9y ago
  >Companies need to make money off of those investments so the compounds that do succeeded might become insanely expensive. The entire process is pretty backwards and I know people who are biochemists in this field who get paid really shitty despite their important work. A lot of money goes to equipment, but a lot also goes to management and cronies in the shops that can fund this stuff. science staff being underpaid relative to the value they provide is the norm. everyone knows the scientists are there for the love of it. the equipment is pricey, sure. million dollar machines, yada yada yada. but the marketing budget is far higher than the r&d budget. it isn't even close. and yeah, it's a mess. from my experience on the inside, companies are willfully deceptive at all phases of the research and clinical trial process. failures are swept under the rug as much as humanly possible. especially if those failures endanger a real person. if a person gets hurt in a trial, i guarantee you that there was knowledge of the risk that was drastically downplayed. drug companies test tens of thousands of candidate drugs before moving to trials. in the last round of testing before trying to move to clinical trials, the drugs are typically very similar variants of each other. problems are found in most. the one candidate where problems aren't found, likely by luck, is the one that advances. survivorship bias is intentionally played up as evidence of validity. then, of course, the "black swan" negative event happens. stock price plummets. cue statements regarding how much they care about trial patients, and the problem couldnt have been foreseen, etc etc. but they knew all along that it would happen. it was happening to mice with the drug's sibling candidates which didn't make it to the clinic.
- nradov 9y ago
  Precision medicine offers some hope here. With cheaper genetic sequencing it's becoming practical to correlate effects and side effects with particular genotypes of the patient or infectious agent. Still though you need a lot of test subjects to isolate the differences.
- jdietrich 9y ago
  Right now, investing in drug development is just a bad use of resources. There's a huge amount of variation in clinical practice using the drugs we already have. A lot of that practice is undoubtedly sub-optimal or actively harmful, but we just aren't funding research into how we use old, boring, generic drugs. If you go into cardiac arrest, you may or may not be given epinephrine. Some hospitals use it in their resus protocols, some don't. Nobody knows whether it works, but it's the subject of heated debate at anesthesiology conferences. Some trials suggest that it's marginally effective, others suggest that it reduces long-term survival rates. There's conflicting evidence on timing and dose. As you teeter on the threshold between life or death, someone might be giving you a drug based on decades-old studies performed on dogs, some clinical guesswork and a bunch of inconclusive research. For the price of one drug that offers a few extra months of life to a handful of patients with a rare form of cancer, we could resolve several of these clinical debates. http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1917810 http://anesthesiology.pubs.asahq.org/article.aspx?articleid=...
arkades 9y ago
> It seems like the key to making medical progress is realizing that not all treatments are "one size fits all" The medical community has realized this, and been tackling this problem for a few millennia. Hippocrates addressed the topic. >and figuring out why treatments that are safe and effective for some people are unsafe for others. That’s the hard part. It’s why we pay attention to how we construct patient recruitment, sample demographics, assess the metabolic pathways by which a drug is processed and study genetic variants in those pathways, develop biologics with different types of chimeric proteins, retrospectively analyze adverse events for patterns, etc. Each and every one of those things that are standard elements of modern medicine and rational drug design are about understanding variability in drug response. We haven’t perfected this yet - nor are we close. Anyone who wishes to lend a brain cell is welcome.
- nonbel 9y ago
  >"we pay attention to how we construct patient recruitment, sample demographics, ... etc" I was told the opposite the other day: "the fact that clinical trials seek people maximally healthy but for the target conditions rather than a representative sample of those with the target condition is a very frequent complaint." https://news.ycombinator.com/item?id=16868660 https://news.ycombinator.com/item?id=16868660 >"Anyone who wishes to lend a brain cell is welcome." Its pretty misleading to promise this. People who disagree with the "publish an endless series of statistically significant differences" paradigm are not going to find it at all welcoming.
  - arkades 9y ago
    > "the fact that clinical trials seek people maximally healthy but for the target conditions rather than a representative sample of those with the target condition is a very frequent complaint." Those aren't quite in contradiction. So, where you start, is with a trial that tries to eliminate meaningful comorbid conditions to allow it to answer the question: "Does this drug work for Disease X?", rather than the question "Does this drug work for Disease X when accompanied by Diseases Y and Z?" There are just far, far too many permutations of X, Y, Z, etc. to allow them all into a study and even pretend to have answered the question about the drug. So, it's not where you start. But, you're absolutely paying attention to patient demographics here, that's part of the point: can we come up with a reasonably homogenous patient pool for step 1? That's not really about being "optimally healthy," it's about homogeneity, except where the latter implies "not a giant variety of comorbid diseases." But, as I hope I've made clear in the way I reiterated it, that's the initial step. Because, hey, we really do need to answer the question about Drug A for Disease X before we start working on the various permutations of Disease X with other diseases. The latter is usually studied through retrospective analysis rather than RCT. Why? A given study has only a certain sample size to work with. There's this sort of odd implicit idea that small sample size is merely an issue of study design, but not really: in practice, a research group only has a catchment area of a certain size - they'll only be able to catch so many patients per unit time, and you can't run a study forever (both because you run out of grant funding and because the state of the disease and therapy moves on.) The more specific you get - e.g., people with Disease X and Y and Z, but neither Y and Z to be more than moderately severe - the fewer patients you can potentially recruit, to the point where the final result is statistically meaningless. This isn't really the worst thing ever: the less capable you are of recruiting patients because of their rarity, the less useful such a study would be to the public because of their rarity. As a practical effect, you can't really build a study to control for every meaningful confounding comorbidity. So, we tend to wait for data to accrue and analyse it retrospectively. It's not as good as an RCT, but it's the best we can do under practical constraints. It's one of those things worth criticizing, in theory, but continues because we don't have the means to do better. Ideally we'd have studies of 20k+ people selecting for significant sub-groups of each permutation of common comorbid conditions. That's just beyond any hope of organizing, running, or paying for. >>"Anyone who wishes to lend a brain cell is welcome." >Its pretty misleading to promise this. People who disagree >with the "publish an endless series of statistically >significant differences" paradigm are not going to find it >at all welcoming. That's simply untrue. I know people working in operations research who are developing novel predictive models for ED patients to predict where they'll need to be sent after workup (and how to prep the appropriate hospital dept. for their arrival, and to estimate when that will be); the VA does shit-tons of operations research. I know people working in the basic sciences who are working on developing ever-more-sophisticated models of the current state of physiology/biochemistry, to allow for increased accuracy of predicting a drug's effectiveness and toxicities before moving on to in vitro testing. And an interesting negative result is about as easily published these days as an interesting positive result (even Easterbrook's big '91 paper on publication bias found that it was for observational and lab studies, but couldn't identify bias in RCT publication.) The full variety of interesting work to be done in clinical trial design isn't super obvious from the outside. Especially since the folks moaning and whining about it tend to be academics, and a big chunk of good clinical trial work doesn't involve many university academics, and the other cool work (e.g., operations research) is being done in industry and at the VA. But "not super visible to university academics, who are the ones talking about publish or perish" and "non-existent" are very different things.

djsumdog 9y ago

Human bodies are vastly different and one of the biggest difficulties is finding compounds that work the same 99% of the time, with minimal but known and treatable side effects. There's a reason this research takes so long. Things might have gotten to market sooner decades ago, but it all comes down to a trade-off with potential good vs safety. When political maneuvering gets in the way, you can get things like the Vioxx disaster. Even with Vioxx, FDA monitoring and procedures did do what they were suppose to in identifying the problem and pulling it off the market. The biggest problem really seems to be money, resources and funding the research. You might discover something promising, but your company will need to pay all those people, buy equipment and purchase animals to go forward. If you get to monkeys and lose a single one, you gotta go back to the beginning. You might find a side effect in 5% that's really bad/serious and your entire compound might need to be scrapped. Companies need to make money off of those investments so the compounds that do succeeded might become insanely expensive. The entire process is pretty backwards and I know people who are biochemists in this field who get paid really shitty despite their important work. A lot of money goes to equipment, but a lot also goes to management and cronies in the shops that can fund this stuff. It's a mess. There needs to be a better, not-for-profit model where a failed compound doesn't matter as much.

barry-cotter 9y ago
> There's a reason this research takes so long. Things might have gotten to market sooner decades ago, but it all comes down to a trade-off with potential good vs safety. Agreed. We’re way past the sane point on the trade off. Aspirin would not pass FDA review under the current regime. Efficacy testing doesn’t appear to do much good but it clearly makes getting a drug to market slower and more costly. For more on this see http://www.fdareview.org/ http://www.fdareview.org/
- HarryHirsch 9y ago
  Efficacy testing doesn’t appear to do much good Come again, it's not important that any medication performs as advertised?! The purpose of Phase II testing is to determine if the new compound is better than placebo; the success rate is ~ 30 %, 70 % are no better than placebo. 70 % of candidates are as good as taking nothing at all. In a public health system this is the most important question to be answered: does the new treatment offer a greater benefit to patients - if not you can't ask the public purse to pay for it. I can also see the risk of backlash - the public perception of bigpharma is already low; if it begins to offer expensive treatments of low value trust in the institutions will erode further.
- arkades 9y ago
  > aspirin wouldn’t pass We have a number of drugs in the same class that are as or more effective with less frequent adverse effects, and the same price to market. It is also one of the leading causes of toxic ODs presenting to the ED. Aspirin shouldn’t pass as an over the counter Anywhere, and wouldn’t but for historical inertia. Don’t confuse familiarity with safety. > efficacy testing doesn’t appear to do much good Efficacy testing is literally how we determine whether a drug works, and what the magnitude of its effects are. Without it, we’d have no idea if a drug worked, if it worked better or worse than competitor drugs, if it worked better or worse for some conditions or sub populations, etc. It’s -the- key information generating step on drugs. This comment is ridiculous to the point of caricature. >fdareview A site from the far-right, unknown-anywhere-but-Fox-news Independent Institute. Can you guess before popping the link open whether they advocate on lightening regulatory burdens on pharma companies?
  - opo 9y ago
    >> aspirin wouldn’t pass >We have a number of drugs in the same class that are as or more effective with less frequent adverse effects, and the same price to market. It is also one of the leading causes of toxic ODs presenting to the ED. Aspirin shouldn’t pass as an over the counter Anywhere, and wouldn’t but for historical inertia. Don’t confuse familiarity with safety. Could you add some more data to back up your statements? For example, you state "It is also one of the leading causes of toxic ODs presenting to the ED" >...During the latter part of the 20th century, the number of poisonings from salicylates declined, mainly because of the increased popularity of other over-the-counter analgesics such as paracetamol (acetaminophen). Fifty-two deaths involving single-ingredient aspirin were reported in the United States in 2000; however, in all but three of these cases, the reason for the ingestion of lethal doses was intentional—predominantly suicidal. https://en.wikipedia.org/wiki/Salicylate_poisoning https://en.wikipedia.org/wiki/Salicylate_poisoning Considering that literally thousands of tons of aspirin are consumed every year, this safety record likely compares well with other drugs. As a comparison, the most commonly used alternative to aspirin is acetaminophen and that is certainly much more dangerous: >...Many over-the-counter and prescription-only medications contain paracetamol. Because of its wide availability paired with comparably high toxicity, (compared to ibuprofen and aspirin) there is a much higher potential for overdose.[88] Paracetamol toxicity is one of the most common causes of poisoning worldwide.[22] In the United States, the United Kingdom, Australia, and New Zealand, paracetamol is the most common cause of drug overdoses.[17][89][90] Additionally, in both the United States and the United Kingdom it is the most common cause of acute liver failure.[91][7] https://en.wikipedia.org/wiki/Paracetamol_poisoning https://en.wikipedia.org/wiki/Paracetamol_poisoning >...A site from the far-right, unknown-anywhere-but-Fox-news I agree with you that efficacy testing of potential new drugs is important, but adding a statement with pejorative labelling like this feels somewhat like you are simply trying to poison the well.
HarryHirsch 9y ago
There needs to be a better, not-for-profit model where a failed compound doesn't matter as much Phase II/III clinical testing is expensive, and the failure rate (i.e. low efficacy, compound simply doesn't perform as expected, and certainly no better than what's already at market) is high. That's what it is, there isn't much that can be done at that front. Thankfully a few months ago Goldman Sachs directly addressed the elephant in the room: pharma yields bad returns, investment in pharma is inadvisable. There needs to be a different financing model, perhaps from the public purse.
- refurb 9y ago
  There needs to be a different financing model, perhaps from the public purse. How does that solve the issue at hand? As you said, development is expensive and has a high failure rate. Why would public funding change either one of those?
  - HarryHirsch 9y ago
    New antibiotics are high on the list of things that are needed, but they will only be used as treatment of last resort, this is where the traditional investment model fails. Development is too expensive to ever recover the outlays. Right now science can't do anything about the high failure rates in Phase II and Phase III trials. The problem isn't to come up with a compound against your target of choice, it's that apart from clinical trials we don't have a way to predict if in real life it will perform better than placebo (Phase II) or adequately (Phase III).
    - Fomite 9y ago
      While commonly used as an example, I'll note this isn't actually even always true for antibiotics. The development of Fidaxomicin/Difficid is actually an example of a fairly inexpensive clinical trial (by clinical trial standards), and Merck didn't buy Cubist for $9.5 billion for a drug they don't think will recover their outlay.
  - tikhonj 9y ago
    At the very least it would spread the cost out over everyone rather than just the people who end up needing the drugs that pass the expensive process.
cryoshon 9y ago
>Companies need to make money off of those investments so the compounds that do succeeded might become insanely expensive. The entire process is pretty backwards and I know people who are biochemists in this field who get paid really shitty despite their important work. A lot of money goes to equipment, but a lot also goes to management and cronies in the shops that can fund this stuff. science staff being underpaid relative to the value they provide is the norm. everyone knows the scientists are there for the love of it. the equipment is pricey, sure. million dollar machines, yada yada yada. but the marketing budget is far higher than the r&d budget. it isn't even close. and yeah, it's a mess. from my experience on the inside, companies are willfully deceptive at all phases of the research and clinical trial process. failures are swept under the rug as much as humanly possible. especially if those failures endanger a real person. if a person gets hurt in a trial, i guarantee you that there was knowledge of the risk that was drastically downplayed. drug companies test tens of thousands of candidate drugs before moving to trials. in the last round of testing before trying to move to clinical trials, the drugs are typically very similar variants of each other. problems are found in most. the one candidate where problems aren't found, likely by luck, is the one that advances. survivorship bias is intentionally played up as evidence of validity. then, of course, the "black swan" negative event happens. stock price plummets. cue statements regarding how much they care about trial patients, and the problem couldnt have been foreseen, etc etc. but they knew all along that it would happen. it was happening to mice with the drug's sibling candidates which didn't make it to the clinic.
nradov 9y ago
Precision medicine offers some hope here. With cheaper genetic sequencing it's becoming practical to correlate effects and side effects with particular genotypes of the patient or infectious agent. Still though you need a lot of test subjects to isolate the differences.
jdietrich 9y ago
Right now, investing in drug development is just a bad use of resources. There's a huge amount of variation in clinical practice using the drugs we already have. A lot of that practice is undoubtedly sub-optimal or actively harmful, but we just aren't funding research into how we use old, boring, generic drugs. If you go into cardiac arrest, you may or may not be given epinephrine. Some hospitals use it in their resus protocols, some don't. Nobody knows whether it works, but it's the subject of heated debate at anesthesiology conferences. Some trials suggest that it's marginally effective, others suggest that it reduces long-term survival rates. There's conflicting evidence on timing and dose. As you teeter on the threshold between life or death, someone might be giving you a drug based on decades-old studies performed on dogs, some clinical guesswork and a bunch of inconclusive research. For the price of one drug that offers a few extra months of life to a handful of patients with a rare form of cancer, we could resolve several of these clinical debates. http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1917810 http://anesthesiology.pubs.asahq.org/article.aspx?articleid=...

arkades 9y ago

> It seems like the key to making medical progress is realizing that not all treatments are "one size fits all" The medical community has realized this, and been tackling this problem for a few millennia. Hippocrates addressed the topic. >and figuring out why treatments that are safe and effective for some people are unsafe for others. That’s the hard part. It’s why we pay attention to how we construct patient recruitment, sample demographics, assess the metabolic pathways by which a drug is processed and study genetic variants in those pathways, develop biologics with different types of chimeric proteins, retrospectively analyze adverse events for patterns, etc. Each and every one of those things that are standard elements of modern medicine and rational drug design are about understanding variability in drug response. We haven’t perfected this yet - nor are we close. Anyone who wishes to lend a brain cell is welcome.

nonbel 9y ago
>"we pay attention to how we construct patient recruitment, sample demographics, ... etc" I was told the opposite the other day: "the fact that clinical trials seek people maximally healthy but for the target conditions rather than a representative sample of those with the target condition is a very frequent complaint." https://news.ycombinator.com/item?id=16868660 https://news.ycombinator.com/item?id=16868660 >"Anyone who wishes to lend a brain cell is welcome." Its pretty misleading to promise this. People who disagree with the "publish an endless series of statistically significant differences" paradigm are not going to find it at all welcoming.
- arkades 9y ago
  > "the fact that clinical trials seek people maximally healthy but for the target conditions rather than a representative sample of those with the target condition is a very frequent complaint." Those aren't quite in contradiction. So, where you start, is with a trial that tries to eliminate meaningful comorbid conditions to allow it to answer the question: "Does this drug work for Disease X?", rather than the question "Does this drug work for Disease X when accompanied by Diseases Y and Z?" There are just far, far too many permutations of X, Y, Z, etc. to allow them all into a study and even pretend to have answered the question about the drug. So, it's not where you start. But, you're absolutely paying attention to patient demographics here, that's part of the point: can we come up with a reasonably homogenous patient pool for step 1? That's not really about being "optimally healthy," it's about homogeneity, except where the latter implies "not a giant variety of comorbid diseases." But, as I hope I've made clear in the way I reiterated it, that's the initial step. Because, hey, we really do need to answer the question about Drug A for Disease X before we start working on the various permutations of Disease X with other diseases. The latter is usually studied through retrospective analysis rather than RCT. Why? A given study has only a certain sample size to work with. There's this sort of odd implicit idea that small sample size is merely an issue of study design, but not really: in practice, a research group only has a catchment area of a certain size - they'll only be able to catch so many patients per unit time, and you can't run a study forever (both because you run out of grant funding and because the state of the disease and therapy moves on.) The more specific you get - e.g., people with Disease X and Y and Z, but neither Y and Z to be more than moderately severe - the fewer patients you can potentially recruit, to the point where the final result is statistically meaningless. This isn't really the worst thing ever: the less capable you are of recruiting patients because of their rarity, the less useful such a study would be to the public because of their rarity. As a practical effect, you can't really build a study to control for every meaningful confounding comorbidity. So, we tend to wait for data to accrue and analyse it retrospectively. It's not as good as an RCT, but it's the best we can do under practical constraints. It's one of those things worth criticizing, in theory, but continues because we don't have the means to do better. Ideally we'd have studies of 20k+ people selecting for significant sub-groups of each permutation of common comorbid conditions. That's just beyond any hope of organizing, running, or paying for. >>"Anyone who wishes to lend a brain cell is welcome." >Its pretty misleading to promise this. People who disagree >with the "publish an endless series of statistically >significant differences" paradigm are not going to find it >at all welcoming. That's simply untrue. I know people working in operations research who are developing novel predictive models for ED patients to predict where they'll need to be sent after workup (and how to prep the appropriate hospital dept. for their arrival, and to estimate when that will be); the VA does shit-tons of operations research. I know people working in the basic sciences who are working on developing ever-more-sophisticated models of the current state of physiology/biochemistry, to allow for increased accuracy of predicting a drug's effectiveness and toxicities before moving on to in vitro testing. And an interesting negative result is about as easily published these days as an interesting positive result (even Easterbrook's big '91 paper on publication bias found that it was for observational and lab studies, but couldn't identify bias in RCT publication.) The full variety of interesting work to be done in clinical trial design isn't super obvious from the outside. Especially since the folks moaning and whining about it tend to be academics, and a big chunk of good clinical trial work doesn't involve many university academics, and the other cool work (e.g., operations research) is being done in industry and at the VA. But "not super visible to university academics, who are the ones talking about publish or perish" and "non-existent" are very different things.