Clinical Trials ~ Lies, Damn Lies and STATISTICS ~ and data we need for melanoma decisions and treatments...

We all need real live data, proven factual information, in order to make reasonable choices about our health, needed treatments, medication, safety information on the vehicles we drive, the restaurants at which we choose to eat, and ever so many other daily decisions - large and small!  Data is important and should not be buried or fudged to attain outcomes preferred by invested parties.  When you are diagnosed with a deadly disease, you need real, tangible information in order to make the best informed decisions you can regarding your care.  I wrote this in 2012:  Educated guesses and desperate decisions..... Being a rattie in a Phase 1 clinical trail of Nivolumab (Opdivo) from December 2010 - June of 2013 was an extreme learning experience to say the least!  As a medical professional of many years, always accompanied by another, I am horrified to think of what folks without such backgrounds deal with in that circumstance.  As it was we were definitely swimming upstream during that process!  And while I am certain access and participation in that clinical trial absolutely saved my life, the management of clinical trials runs the gamut from incredible science to completely ludicrous to intensely horrifying!  Here are just a few of my rants regarding clinical trials over the years:

July 2013:  Almost 50% of Results of Cancer Drug Trials NOT published!
March 2014:  Should Melanoma Brain Met patients be allowed in clinical trials???
April 2014:  Clinical Trials and Patient Rights...An oxymoron????
December 2014:  Patient rights in a clinical trial. An oxymoron???? Redux...
January 2015:  A beautiful lady, with eloquent, though heartbreaking words re: clinical trials....
January 2016:  The Problem with Clinical Trials
August 2016:  Medical studies in children go unpublished!!! Here we go AGAIN!!!
September 2016:  New Rules to push for published trial results!
January 2017:  The trial of trials!
June 2017:  Outcomes for melanoma patients ~ clinical trials vs standard of care
April 2018:  Odds and Ends ~ Melanoma in children and cancer trial access for people of color

Sadly, many of these reports touch on points that remain unresolved!  Just last week, Medscape posted:  Most Clinical Trials Still Don't Report Results by Deadline  Despite the many lives at stake, the report notes:  "Three years after a federal deadline was clarified, mandating that clinical trial sponsors report results to ClinicalTrials.gov within 1 year of the primary completion date, most researchers still miss the deadline, ...  [To examine this issue, researchers]  ... downloaded all registered trials due to report between March 2018 and September 2019 and found that of those 4209 trials, only 40.9% made the 1-year deadline; only 63.8% reported results at any time."

Horrifying, no??  And even when researchers report trial findings, what do those results really mean?  Does 1 + 1 really = 2 mathematically???  Sometimes not!!!  Back in March of last year, 800 scientists signed a group letter calling for an end to ridiculous statistical massaging of data.  Here's a report on their thoughts from Nature:  Scientists rise up against statistical significance  The authors note:   "For several generations, researchers have been warned that a statistically non-significant result does not ‘prove’ the null hypothesis (the hypothesis that there is no difference between groups or no effect of a treatment on some measured outcome). Nor do statistically significant results ‘prove’ some other hypothesis. Such misconceptions have famously warped the literature with overstated claims and, less famously, led to claims of conflicts between studies where none exists."  Noting that in the end it was their hope, that - "Decisions to interpret or to publish results will not be based on statistical thresholds. [rather] People will spend less time with statistical software, and more time thinking."

And if the math and conclusions involved are reported AND meet "statistical" and "common sense" significance, does the issue or the drug examined even matter?  I could write reams on the first.  Studies that look at obvious issues and derive obvious conclusions, like:  "Folks who consume more calories weigh more than those who don't!!!"  or  "Children whose parents spend more time with them do better in school and life!!"  or  "Peeps who eat their fiber POOP!"  Real studies people.  Wouldn't even kid you!!!  Apart from that - are the treatment or drug options developed and studied even needed?  Unfortunately, there are many instances when you could argue - NOT!!!  This opinion piece from September 2019 in STAT, touches on that very point:   Enough with the me-too drugs. New treatments should be worthy of the people who invest their lives in clinical trials

  "...I believe are too many companies pushing mediocre and me-too drugs, also known as copycat drugs, into clinical development where they will likely fail.  Clinical trials are more than a way to test new therapies. They offer very sick people hope and a chance for more time with their loved ones. Lately, the drug development process has turned into an exercise in me-tooism — at patients’ expense. It’s time to shift the focus back to those who matter most."  With the author noting that in a panel discussion, the head of the FDA  - "called for companies to reevaluate their current clinical trial processes. He rightfully criticized the industry’s repeated attempts at testing an approach in a disease indication after it has failed multiple times.  [As an example, he pointed out] ... "checkpoint inhibitors (drugs that target PD-1 or PD-L1) for multiple myeloma. Three recent studies were conducted close together, and although they were well-controlled and well-managed with data safety review boards, multiple studies showing negative results were not needed...  There is no question that replicating studies has value, but in this situation the industry was duplicating harm to patients, as all three studies showed decrements in overall survival.  ... When people enroll in cancer clinical trials, they are placing their lives in our hands. Many have advanced disease and turn to a clinical trial for hope and possible healing. Yet as an industry, we are competing for these patients to test me-too drugs with significant toxicity, sometimes based on marginal preclinical data.  ...patients are not a company’s resource. ... They are people who are hoping for a chance at recovery, or at least more time with their families with reasonable quality of life. We should treat patients who volunteer for clinical trials the way we would treat our mothers or husbands or best friends.  [He] asked companies to be more efficient by collaborating, sharing data, and conducting platform trials. Some biopharmaceutical companies are trying to do this, but the industry has a long way to go. We should be moving drugs into clinical development only when there’s a strong understanding of disease biology and substantial evidence that a drug has the potential to truly improve lives."

Even when trials meet all of the desired criteria - how does the information attained address the individual?  After all, it is pretty clear that the disease process and treatment response (in terms of disease control and adverse events) varies greatly person to person despite group outcomes.  In the summer of last year, The Scientist published this:  N-of-1 Trials Take on Challenges in Health Care, where the author notes "... an N-of-1 trial [is] focused on the collection of treatment-response data in a single patient, this relatively little-used trial design represents the ultimate form of patient-centered medicine."  Pretty interesting stuff and probably most valuable in tweaking care for a particular patient though they could also elucidate trends when similar results are found among multiple individuals.

So, if you're still with me - and still need to find a clinical trial option that is right for you, there remains the difficulty of learning about available trials and dealing with all the "exclusions" once you've found a trial that seems as though it could be helpful.  If you've already had this medication or that one...you may be excluded.  If you can't do the prescribed number of jumping jacks...then nope.  This trial is not for you.   For the longest, folks with brain mets and CNS disease were kept out of melanoma trials.  Why????  If you are seeking care for a hang nail, then perhaps participation in an experiment with a medication that may cause awful and at times lethal side effects would be over-the-top and ill advised.  However, if you are going to DIE (no doubt about it) without effective treatment, shouldn't those peeps be allowed access to experimental treatments if that is what they want to do???  (Yes, several states now have "Right to Try" laws, but even when patients attain care under their cover, insurance companies, often say, "No thanks, you're on your own!" which shuts down access right then and there!)  Or, do we simply exclude those likely to have untoward outcomes because of their advanced disease, limited physical strength, or prior treatment failures so as to prevent poor statistical results that will reflect badly on the institution, researcher, or BIG pharma who happens to be running the trial?  In prior rants included above, I've noted that researchers can easily group such patients in an arm of their own so as to clarify outcomes.  In the category of  ~  for what it's worth ~ I saw this in Forbes:  Developers Use Artificial Intelligence To Match Patients To Clinical Trials

Despite all that is difficult, negotiating and participating in a clinical trial IS doable!!  Even if you have to do it on your own.  Here are some thoughts I put on MPIP for a forum member not too long ago:

Whether or not one wants to pursue a clinical trial option depends on many things.

1. First and foremost would be whether or not there is a viable treatment option for your condition. Back in the dark ages of melanoma (before 2011) when there were NO FDA approved treatment options other than interferon (which did absolutely nothing to improve OS and made you sick as a dog) or IL2 which, as administered back then, required a stay in the intensive care unit and a potential 10% response rate and given its toxicity wasn't an option unless you were Stage IV, we all wanted a chance at a treatment via a clinical trial as ipi and nivo were cooking along there and outcomes to them were looking better than the drugs otherwise available.  Now that immunotherapy and targeted therapy drugs are FDA approved for melanoma, the landscape has changed. So, as a starting point, if you have viable treatment options with odds that are as good or better than current trial drugs - regular standard therapy is generally preferred.

2. Personality and money. Clinical trials are not for the faint of heart. They are their own crazy in addition to the treatment. Plus, they can be expensive. Most are not "free" as many may think. Pricing is variable, but for my nivo trial in 2010 the only thing that was "given" to me was the trial drug and the labs THEY wanted to draw for the study. All other expenses (from nursing in the unit, to IV tubing, to doctor visits, to REQUIRED for participation scans and labs - not to mention travel to the location) were my problem. If my insurance company covered them great. But if they didn't and/or costs like deductibles and patient percentages were required - they were mine to pay. Further, most trial paper work comes with a disclaimer that states if you grow three heads, have side effects, or any other untoward event - the coverage for diagnosing and treating that event is NOT the responsibility of the doc or institution running the trial nor the drug manufacturer. So, that's fun. You really have to pay attention to the fine print.

3. Understanding what you are offered. Phase 1 trials are basically dosing trials. They are not technically done to see who they cure, rather they are done to determine the amount of medication needed to get a response versus the amount of drug that makes people freak. Using my phase 1 nivo trial as an example - We were divided into 3 arms of Stage IV patients with active disease and 3 arms of Stage IV patients who had their disease removed via surgery or radiation. The first arm of both cohorts got only 1mg/kg of the drug. When we did not spontaneously combust, the next got 3mg/kg. The third got 10mg/kg. The results of this and other studies at that time led to the use of the 3mg/kg dosing schedule which has now been rounded to the 240 mg dose every 2 weeks or the 480 mg dose every 4. Additionally, the drugs used in Phase 1 trials are relatively new with little data in humans to back up their use. So, there is a risk that they will not benefit the rattie as much as desired. HOWEVER, the good thing about Phase 1 trials is that everyone gets the drug. In Phase 2/3 trials - the trial drug is often randomized. With some arms getting nothing or a lesser drug. The recent/ongoing trials for ipi/nivo as adjuvant for melanoma are a pretty good deal because the participants get either the desired combo or nivo alone. So even if you get "only" the nivo arm, you are still getting a good treatment. Unfortunately, not all trial options are that good. I've ranted for years about everybody and his brother putting valid trial drugs for melanoma up against dacarbazine (a drug known to have little effect). Something that I feel at this point in time is simply unconscionable!!! I digress, but you get the idea.

4. Your doc's role. Your doctor, if they deserve the license under which they practice ABSOLUTELY SHOULD discuss trial options with their patients when appropriate and help find the one that will best suit their patient's needs!!!!!!!!!!!! However, the odds of attaining this service with a local oncologist is small. If things get beyond the treatment options they have available, they will usually just send the patient to a bigger facility that does more research - which I guess is okay. The patient can then meet with docs who are more specialized and who have access to clinical trials. NOW - THOSE docs should still be frank about how good a fit the trials at their institution may or MAY NOT be for the particular patient. Some docs are. Some aren't. I've experienced both. Sadly, many will simply try to enroll you in what they are running, rather than telling you about trial options elsewhere that may actually be better for you. I can say with complete authority that Jeff Weber, currently of NYU, is a straight shooter whom I have known to tell patients when appropriate, that what he has open currently is not really their best bet, BUT the trial being run by so-and-so would be a better option and hook them up with the other physician.

5. Trial navigators can be used to help patients find trials they need. I have mixed opinions on this one, because - like the docs - some do a really good job and some do not. Many institutions and foundations have this service. In fact, I believe MRF has some.

6. There is no advocate for the patient better than the patient - if you or a family member is able physically and mentally to do the task. Searching for trials can be absolutely daunting. But, it is doable for many. This site: https://clinicaltrials.gov/ - is fairly navigable. You can put in your disease and stage. You can put in a particular drug if you like. You can put in "recruiting" as a filter. For instance - here is what it looks like for Stage IV melanoma, actively recruiting trials: https://clinicaltrials.gov/ct2/results?recrs=ab&cond=Stage+IV+Melanoma&t... 198 trials are listed. You can click on each one. When you do that you will see the drugs used and the arms offered. You can google the drugs as needed to see what sort they are. Below that, inclusion and exclusion criteria are listed. Below that, all locations at which the trial is being offered is noted - across the globe - not just the US. A trial coordinator is often listed as well. I always tell folks - if you are at all interested in a trial - CALL!!!! Even if you are not certain you WANT to do it or if you actually qualify. It never hurts to ask questions and learn more. My husband found all the trial options I ever looked at in this manner.  In fact, he found the Phase 1 nivo trial I participated in when calling the coordinator about an entirely different trial!!

I was lucky.  But, you can be too!!!  Ratties rule!!  Blessings to each of you. - celeste