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With a major pandemic sweeping the world, the standard process of clinical trials for drug approval has come under criticism as a needless source of bureaucracy and delay. Drug discovery chemist Derek Lowe in a blog post explains how clinical trials for drug approval work and the reasons behind the various requirements that the FDA and equivalent organisations around the world generally put in place before approving a new drug. He explains how most of these apparently pointless bureaucratic hurdles are actually there to help protect the integrity of the scientific process and ensure that the human subjects undergoing the trials are treated ethically. While a case can be made for relaxing some of these safeguards, especially in this time of pandemic, it is probably not a good idea to do so without at least understanding what these safeguards are for.
Determining how much of a pharmaceutical is needed to prepare for the trial. Ensuring your are actually preparing just that drug and not a polymorph. Proper laboratory and manufacturing practices to ensure the desired drug is actually prepared without impurities and contaminants. Preparing a plan for a drug trial. Demographics — age, gender, weight, current medications being taken. Getting a representative distribution of these as participants. And there's much more.
(Score: 5, Insightful) by aristarchus on Saturday May 02 2020, @10:17PM (13 children)
There is a reason clinical trials have to be so complicated. The primary one is that Pharma companies are greedy. They will fake results given the chance, because billions of dollars are at play! We have seen this among the investing class here on SoylentNews, with Sulla and others speculating on what stocks of what companies to buy.
Second, fear and paranoia. Sick people are easy marks, and "I told you I was sick" people even more so. They need to be protected from unscrupulous snake oil peddlers, Fox News, and the President of the United States, Impeached.
Third, emotional investment by researchers. Even Dr. Didier Raoult probably has an egoistic interest in his research being successful, and thus saving lives. Non-medical researchers are not so emotionally tied up in outcomes. Between the researchers wanting positive results, and the patients in a trial desiring positive results, a double whammy of confirmation bias ensues.
Conclusion, Clinical Trials are not overly complicated. Any one who says so is no doctor, is no medical professional, and probably is a anti-regulation Libertard-Republican looking to make big bucks off of death and dying, fear and paranoia.
(Score: 4, Interesting) by JoeMerchant on Saturday May 02 2020, @10:41PM (5 children)
My favorite "told you so" moment in an FDA application was when the data for a new product, patented and developed by a single M.D. who owned a majority stake in the company was all collected and analyzed by the same M.D. I advised the CEO in no uncertain terms: what you're trying to do here is a complete and total conflict of interest, there's no way they're going to approve this, response: "getting other doctors to collect and analyze the data is too expensive, we have to at least try to submit like this." Yeah, o.k. burn 6 months of development runway while you get your rejection. Oh, and burn another 90 days by failing to file an extension request by the deadline - kids these days (CEO was 27) think that bureaucrats are soft-touches like their parents, I guess they have to learn somehow.
🌻🌻 [google.com]
(Score: 4, Interesting) by anubi on Sunday May 03 2020, @01:03AM (1 child)
I've always felt that responding with exactly as you see it, not what you think they want to hear, is in the long run the best policy, even if in the short run you have to find another job.
Office politics is a bear that i have never successfully fought.
Clinical trials take so long for the same reason I take so long. I want to make damned sure I don't release half baked work. Trouble is a lot of executive-class people demand half-baked work in the interest of quarterly profit goals and bonuses.
You sound like the kind of guy who is satisfied with nothing less than the best, lots of A's, Dean's List, and so on...and did your own work, not copy someone else's. Simply because you did not trust it.
It took lots of time to do it this way, but there is a comfort in knowing it's done right. It's tough for people of this mindset to subordinate to someone else who prides themselves in making the quick buck by cheapening the product.
Anyone think Elon Musk or Bill Gates would have made a decent employee?
Anyway, that's a great post, seen from the inside, of how half-baked stuff makes it out if proper checks and balances are not in place.
My hope is they run the clinical verifications, do it right, and give it to me straight...regardless of the outcome or investor interests.
"Prove all things; hold fast that which is good." [KJV: I Thessalonians 5:21]
(Score: 2) by JoeMerchant on Sunday May 03 2020, @03:54AM
I work for a big place now, and that's their HR approved messaging "from the top down," and, they're not wrong... even though human nature tends to avoid the confrontation in bringing bad news.
Yes, and no. If I won a major lottery, I'd probably devolve into perfectionism because I enjoy it. Back in the real world, doing the most good for the most people usually involves knowing when to cut and run, accepting the minor flaws for the greater good. That same big company takes mistakes very seriously and really strives to avoid embarrassment (which is horrible for innovation, we end up expanding/innovating by acquisition 90% of the time), but... they also develop and refine policies to review product and accept "acceptable imperfections" in recognition of the fact that a product that never ships never does any good for anybody, and we make stuff that's complex enough that it's never perfect.
🌻🌻 [google.com]
(Score: 2, Interesting) by Anonymous Coward on Sunday May 03 2020, @05:29AM (2 children)
I ran into one of those. I did the blind statistical analysis on the equivalent of preregistered study. Crunch the numbers according to the scope. I got back an email requesting a particular "Tee Test." Now, a t-test of any kind would have been totally inappropriate, especially without being in the registered protocol without justification. I refuse, while copying the appropriate people to cover my ass, and rescind permission to my previous work.
Months later, I get a call. "Hello, AC. I'm $VERY_IMPORTANT_PERSON. So I'm looking at some stuff here and it looks ... Well ... I'll just put it this way, did you do analysis for $STUDY?" I told them I emailed them months ago about it. Situation diffused, they catch me up. Turns out the person redid the analysis and left out every single comparison measure except for the t-test they asked me about. Turns out that was the only comparison found with significant results if uncorrected. They then lied to cover their ass and tried to throw me and other collaborators under the bus. Ended up costing them everything once their reputation was shot.
I just laughed so hard when I got a copy of their work. Looked like they followed a walkthrough online of how to do the basics in R and put what that spit out into the document. Nobody cares about your descriptives for unused variables, variable Q-Q plots or the mean of ordinal, non-interval variables. Trying to baffle them with bullshit so they wouldn't notice the meat was missing, I guess. And it probably just ended up calling more attention to the fact it wasn't there.
(Score: 5, Informative) by rleigh on Sunday May 03 2020, @09:18AM (1 child)
I've seen this in academic research as well. I've seen people trying different statistical tests until they find one which is significant. Stuff like using U tests where a T test would be appropriate. "But you can't do that, your data is parametric and it's clearly not significant. Sorry, but your data is simply not showing what you want it to show". "Well, it's publishable if it's significant, and the U test shows significance". Shocking. And this was for medial research as well, so it would have potentially influenced clinical studies. It's no little wonder that so much published life sciences work is later retracted. It's marginal at best. At worst, it's fraudulent. But the pressure to publish is so great, too many people try to bend the rules. It's one of the reasons why I didn't succeed as an academic. I outright refused to publish incomplete or misrepresentative data, which didn't make me popular.
A friend of mine went to the US to work for the NIH on some postdoc. Couldn't reproduce the previous postdoc's research, but was supposed to continue that line of investigation. After spending months trying to reproduce their results, they basically found that they fabricated everything. They raised this, but the previous postdoc had gone on to a high profile position and start actual clinical trials based upon this fraud. He ended leaving academia; doing the right thing is a career-ending move. No results to show for that postdoc? Out. Doesn't matter that you're actually a good researcher. That person not only killed the career of at least one promising scientist, they actually started human clinical trials based upon a complete fabrication.
I've also worked for a pharma company on various drug screening assays. I would have so say, they were far more diligent about good experimental design and statistics than academics. They employed full time staff for data analysis and statistics, as well as scientists. The accuracy of the results determined which drugs would proceed further in the pipeline, so they genuinely cared about not picking a dud which would fail down the line. They had the opposite problem. Despite making better and more detailed experimental models for assays (high-content screening), drug performance in cell-based assays was not sufficiently predictive of behaviour in whole animals or human trials. A drug could kill cancer cells like no tomorrow on an assay plate, yet be ineffective (or toxic) in reality.
So based upon these experiences and observations, I'm happy that there is a high bar to meet. There's too much untrustworthy nonsense out there. The trial has to independently prove the safety and efficacy of the treatment. I'm sure that some of the red tape could be cut; not all of it is strictly necessary, and some of it is to raise the bar to competition, but that would need to be done very carefully to not remove some of the strictly necessary barriers.
(Score: 2) by JoeMerchant on Monday May 04 2020, @12:46AM
They know the value of C'ing their A's... a lot to lose when you're a Trillion dollar enterprise.
🌻🌻 [google.com]
(Score: -1, Flamebait) by Anonymous Coward on Saturday May 02 2020, @11:25PM (2 children)
They need to be protected from unscrupulous snake oil peddlers, Fox News, and the President of the United States, Impeached
Because, yeah...fuck having any hope. You should be WANTING this shit to work. Yet you seem to have a different attitude on it. Why is that? Did your bitch lose the 'in the bag election'?
You have to look no further than the current accusation against Biden. We went pretty damn quick from 'believe all women' to 'welllll acccchtuuuuly'. That pretty much proves all of this histrionics has zero to do with actual issues. It is 'wah wah wah we lost'. Throw whatever shit at anyone. Make sure it sticks.
Impeached
And exonerated. For 'hey that looks like a crime look into it'. Sure do not see anyone pissed off what Biden and his son were up to. Even *if* Trump did something wrong, so did they. But lets not talk about that. It was just as BS as the one they did against Clinton.
(Score: 0) by Anonymous Coward on Saturday May 02 2020, @11:29PM (1 child)
> You should be WANTING this shit to work.
You proved his point - you're all stakeholders in the outcome and can't be trusted.
(Score: 0) by Anonymous Coward on Sunday May 03 2020, @12:34AM
Duh. That's why politics exists. We're all biased and is impossible to trust each other's motivations, so we have to conjuring's and try to figure out acceptable solutions.
(Score: 4, Interesting) by Anonymous Coward on Sunday May 03 2020, @01:26AM (3 children)
Greed is not solely tied to one side of the political spectrum. Big money is a powerful temptation to commit research misconduct regardless of political party.
Dr. Fauci has been promoting the results from one remdesivir clinical trial [statnews.com], saying there's clear-cut evidence that remdesivir works. It would be good to know whether or not he has any financial interest in Gilead. So far, I haven't been able to find this information.
There's good reason to question the results of this clinical trial. There are experimental design of one of the Gilead trials [statnews.com] of remdesivir. Leaked results from a trial in China showedno evidence that remdesivir is beneficial for coronavirus patients [statnews.com]. In the study Dr. Fauci is referencing, the standard for evaluating the efficacy of the drug was changed during the study [washingtonpost.com] from tracking the number of deaths or patients on ventilators to the mean recovery time. While a statistically significant difference was reported in mean recovery time, the difference in the death rate was not statistically significant. Scientists have raised concerns about approving the drug prior to releasing the data from the trial [qz.com] for other scientists to examine. Dr. Fauci chose to release the results early like he did [reuters.com] out of concerns about the results being leaked.
I hope remdesivir really does have efficacy at treating the coronavirus. But there are a lot of trials with questionable methodologies producing conflicting results about drugs like hydroxychloroquine and remdesivir. While some studies claimed that hydroxychloroquine is effective, a large study at the VA suggests it has no benefit in preventing patients from being placed on mechanical ventilators [medrxiv.org]. It's also worth noting that the standard in the VA study of whether patients are placed on mechanical ventilators is different from the standard in the remdesivir study.
My intuition is that Dr. Fauci was just excited about the first study showing a statistically significant positive result versus a placebo for treating the coronavirus. But the question about conflicts of interest is still valid. I'm a researcher in a different field, working in academia. Yesterday, I received a notification that a proposal I submitted a few months ago has been recommended for funding. Before my university processes the award, I'll need to fill out a form disclosing any potential conflicts of interest. And I'll be required to submit a new form every year disclosing any conflicts of interest. Scientists are expected to disclose possible conflicts of interest. Dr. Fauci has been a principal investigators on other awards and didn't have any relevant financial disclosures, but I couldn't find specific information if he has a financial interest with Gilead. Dr. Fauci is a fellow scientist and it's completely fair to ask scientists if they have conflicts of interest.
(Score: 5, Interesting) by Anonymous Coward on Sunday May 03 2020, @02:05AM (1 child)
Has Fauci been "pushing" this drug? I give him a lot of slack given the fine line he has to tread. He has to delicately caveat and temper false hope spouted out of the President, but do it in a way that doesn't embarrass him. Plus he is under tremendous pressure to "wrap all this up" and put a happy spin on everything.
By the way, I work in the Federal Government and every year I have to take an ethics training as well as file a financial disclosure form. Do you know how galling it is under this administration to sit through an ethics course and filling out my disclosure form when our "bosses" flagrantly ignore all of it without ANY repurcussions? It is pretty demoralizing, actually.
(Score: 5, Insightful) by hendrikboom on Sunday May 03 2020, @02:59AM
And that's how a culture of corruption gets established and propagates itself. By demoralizing the honest.
(Score: 1, Interesting) by Anonymous Coward on Sunday May 03 2020, @06:13AM
I've defended the new Remdesivir results. There are key differences in that study compared to many others, but we will have to see the actual preliminary results before anything can really be said. With that out of the way, changing the primary measures happens in studies, especially switch a primary and a secondary. Now, they are correct that this is usually very suspicious because it suggests blinding has been removed or something else fishy is going on, but the preliminary results should give a much better picture of who, when, where, why, and how it was changed.
In addition, there are key differences in this study, according to the public information on it that we have, and ones like the Chinese one in the Lancet. For example, there is a large disparity in group sizes, comorbidity ratios, and other characteristics in the Chinese study that would favor the placebo group. It also had a relatively low statistical power.
To me, this whole thing reeks as the NIAID and the government in general being desperate to come up with something now. The existence of a known mechanism and these preliminary results are an interesting indication that there may actually be something there and is a stark contrast to what came before. When used on patients that aren't nearly as sick, this could be a veritable "miracle drug" such as they can exist. But it is too easy to take shortcuts under political and other pressure. This could just as easily be an ineffective and expensive dud or turn out to net-harm healthier people due to side effects or iatrogenic adverse events.