IS THERE AN ALTERNATIVE TO INFOMERCIALS
DISPLACING SCIENTIFIC PUBLICATION?
By Semmel Weis
First published 25 Jul 2017
Last edited 27 Jul 2017 06:35pm
PERHAPS NOTHING BETTER THAN SAN MIGUEL (2008) IS POSSIBLE?
To the criticisms posted at
TRILOGY of the San Miguel (2008) trilogy, the reply that might be expected from infomercial publishers in general, and from Johnson&Johnson in particular, is that the defects described are inescapable, and for which reason such infomercials must be recognized not only as admissible scientific research, but even as admirable and state-of-the-art scientific research.
More specifically, the Johnson&Johnson side might argue, it is impossible to demand that patients comply with intended drug protocols when it can be seen that such compliance is sickening them, and sometimes killing them — even if critics object that dose reduction, especially down to zero, is a deviation from the intended drug protocol.
And it is impossible to deny Control-Group patients eventual access to the drug being promoted and which patients hope will save their lives — even if critics object that this makes it impossible to determine the long-term survival difference between Bortezomib-Group patients who should have gotten bortezomib during the clinical trial and at no other time, and Control-Group patients who should have gotten it never.
And it is impossible to see patients suffering from adverse reactions without providing them background therapy — even if critics identify that background therapy as a confounding.
And it is impossible to keep patients from dropping out of the clinical trial — even if critics identify that dropping out as non-random, and therefore destructive of an earlier pre-treatment equality of patient characteristics.
And it is impossible for researchers to themselves avoid creating lost subjects by cuttingoff their clinical trial, because clinical trials cannot go on forever and some subjects inevitably are inducted too late to complete their 54-week treatment and on top of that to be observed for the full Months=78 time span of San Miguel (2013) — even if critics claim that the eventual deaths of such cutoff subjects are rendered invisible to Kaplan-Meier analysis, and which invisibility supplies the fuel which feeds Kaplan-Meier inflation of survival curves.
And there is no software other than Kaplan-Meier which will draw decent graphs of data that has suffered large patient losses — even if critics object that Kaplan-Meier curves claim survivorship for patients whom no researcher has seen alive.
And there still remains one more shortcoming of the Miguel (2008) trilogy which has not yet been mentioned, but which is the most important of all, and which shortcoming Johnson&Johnson will most surely claim is utterly impossible to satisfy — and that is a third group of patients that needs to be added, a NO-CHEMO Control Group which gets no chemotherapy at all.
If it were the case that both MP and BMP shorten life, but BMP shortens it less, then a two-group clinical trial testing only MP and BMP — if properly conducted — would discover that BMP patients lived longer than MP patients, but would quite overlook the fact that both treatments shortened life. The more important discovery that both MP and BMP shorten life would be noticed only if a NO-CHEMO Group were added to MP and BMP. However, running a NO-CHEMO group would amount to asking dying patients to go without treatment for Months=78, which is impossible — even if critics complain that in the absence of a NO-CHEMO group, nobody knows how long patients would live without any chemotherapy whatever.
CAN MURINE-MODEL RESEARCH TEACH US ANYTHING?
By way of beginning to address the imagined Johnson&Johnson defense above, let us see if research evidence of an entirely different sort might throw light on the issue, research evidence such as in the following five murine-model (mouse) experiments:
Katz (2015) Bortezomib helps multiple myeloma kill|
Verma (2017) and Demoulin (2017) cure pancreatic cancer using CAR-T NKR-2
Kottke (2011) and Boisgerault (2013) cure prostate cancer by vaccination
Katz (2015) Murine-Model Experiment|
Indicates That Bortezomib Kills
The fundamental question which readers of the bortezomib literature want answered is what effect bortezomib has on the survival of patients with multiple myeloma (MM). Below is a synopsis of the Katz (2015) experiment which indicates that bortezomib shortens the life of multiple myeloma sufferers, at least when the sufferers happen to be mice.
Katz (2015) injected twenty mice with MM cells. In the display below, the twenty mice can be seen in the upper row, and each row lower shows the same twenty mice, only photographed about a week later.
The groups differed in one way only — the duration of their pre-MM exposure to bortezomib. The mice in the left-hand column under the heading "veh" had no bortezomib injected before being infected with MM. ("Veh" stands for "vehicle only was injected", the vehicle being the liquid in which bortezomib is dissolved when bortezomib is being administered.) The mice in the middle column under the heading "4h" had a bortezomib injection 4 hours before their MM injection. And the mice in the right-hand column under the heading "24h" had a bortezomib injection 24 hours before their MM injection.
The groups, then, differed as to how long they had bortezomib flowing through their bodies prior to being infected with MM: either 0 hours or 4 hours or 24 hours.
The images were created using bioluminescent imaging which shows color — in the living mouse — where MM has spread, the blue end of the color scale indicating barely-detectable MM, and the red end indicating heaviest concentration of MM.
The top row, then, shows the twenty living mice Day=15 after MM injection, and as no color is visible, we conclude that the spread of MM in their bodies is as yet undetectable. Moving down to the next line shows the same twenty living mice, Day=22 after MM injection, the appearance of blue showing where MM has begun to be detected, and the blue often appearing first in the base of the tail because the MM was injected into the tail vein. Travelling downward in the display, two trends become apparent — color indicating broader and more concentrated MM invasion, and an increasing number of Xs indicating that the mouse occupying that column has died.
Comparing groups shows that MM killed the 24h mice faster than it killed the 4h mice, and killed the 4h mice faster than it killed the zero-bortezomib mice in the "veh" column. The longer the bortezomib remained in the mice, one might say, the less strength it left them to fight off MM.
Katz et al (2015)
Host response to bortezomib promotes MM aggressiveness in mice. Eight week old CB.17 SCID mice were injected intravenously with 1mg/kg bortezomib or vehicle (veh). Four and 24 hours later mice were inoculated through the tail vein with 5x106 CAG-luciferase+ cells (n=6-7mice/group). Tumor growth and expansion was assessed by IVIS in vivo imaging system.
Ofrat Beyar Katz, Neta Ben-Tsedek, Irit Avivi, Dror Alishekevitz, Michael Timaner, Valeria Miller, Moshit Lindzen, Yosef Yarden, and Yuval Shaked, Bortezomib-Induced Proinflammatory Macrophages Contribute to Multiple Myeloma Cell Aggressiveness, Blood, 2015, 126, 5367.
Had the above experiment resembled San Miguel (2008) by omitting the NO-CHEMO veh group, its recommendation would have been to treat MM with 4h of bortezomib rather than 24h. It takes the NO-CHEMO Veh Group to demonstrate that zero-bortezomib is the best recommendation of all.
It is to be appreciated that Katz (2015) avoided all of the scientific-method violations that ruined San Miguel (2008). Primarily, all Katz (2015) subjects exactly followed their MM-injection and bortezomib-injection protocols. No subjects chewed through the walls of their cages to escape the experiment. The experiment was not cutoff leaving half the subjects unobserved beyond, say, Day=36. No confounding background therapy was administered to alleviate adverse reactions. No Intent-To-Treat assumptions were made of subjects having received treatments that they did not in fact receive. No Kaplan-Meier graphs were brought in to lift survival curves to fantastic heights.
And the superficial indicators of infomercial-quality reseach have vanished as well. A credible 9 authors for Katz (2015) instead of the incredible 21 authors for San Miguel (2008). And a sufficient 6 or 7 subjects per group instead of the needlessly expensive and burdensome 344 and 338. And the Katz (2015) subjects each requiring two injections, and the research spanning only two months, whereas the San Miguel (2008) subjects each required hundreds of injections, and thousands of pills, and over the span of just over one year for the initial treatment, and followed by who knows how many more years of maintenance treatment and then resumed treatment in response to the relapse that everyone knew bortezomib could neither prevent nor beat back, or in response to the relapse that readers of Katz (2015) might expect bortezomib to trigger.
If the welfare of human multiple-myeloma patients were of primary concern to San Miguel and to Johnson&Johnson and to the FDA and to The New England Journal of Medicine, then their conclusion would have to be that although the effect of bortezomib on humans cannot be assumed to be identical to its effect on mice, it is nevertheless safest to fear that it might be similar, and so that alarm bells needed to be rung, and so that at the very least, patients needed to be shown, and to have explained, the above Katz (2015) display and informed that the best guess is that bortezomib might hasten the death of human patients suffering from multiple myeloma the same way it hastened the death of mice suffering from multiple myeloma.
What we have seen so far is that a murine-model experiment can be useful in exposing a harmful treatment, whereas the experiment below will show that a murine-model experiment can also to useful in discovering a beneficial treatment.
Verma (2017) Murine-Model Experiment|
Suggests That CAR-T NKR-2
Cures Pancreatic Cancer In Mice
The claim in TRILOGY that when the effect of the experimental treatment is strong, as few as 5 subjects per group is sufficient, was somewhat supported by Katz (2015) above running 6 or 7 subjects per group, but now will be demonstrated to have been conservative by the example of Verma (2017) being able to demonstrate a clear experimental effect running a mere 4 subjects per group.
T-cells attacking cancer cells
Being tested in Verma (2017) is a Charles L Sentman-developed therapy called CAR-T NKR-2. NK refers to Natural Killer T-cells, which are white blood cells produced by the Thymus (that's where the "T" comes from), and which attack and kill viruses and cancer cells. NKR refers to Natural Killer Receptors which attach to the surface of T-cells and determine exactly what the T-cells will attack and kill, and by implication what they will leave unscathed. NKR-2 T-cells carry a particular Sentman-created set of receptors guiding the T-cell attack. CAR-T therapy removes a sample of T-cells from the cancer-patient's blood, adds to each T-cell a receptor called CAR (Chimeric Antigen Receptor) which will steer the T-cells more accurately to the cancer cells, then infuses the modified T-cells back into the patient's blood stream where they can do their work.
On Day=0, not shown in the display below, the Verma (2017) researchers infected all mice with PANC-1, which is a pancreatic-tumor cell line in use by researchers for more than four decades. On Days 12 and 19, all mice are given an injection, which differs between the three groups. The HBSS group on the left is injected with a placebo. The NKR-2 Group on the right is injected with T-cells bearing the NKR-2 receptors expected to perform best in destroying the pancreatic cancer. The group in the middle column receives a curative treatment expected not to be as good as NKR-2. The big horizontal arrows on the left indicate that on Days=12 and 19, all mice get the infusion appropriate to their group, although the arrows mentioning only "NKR-2" draws particular attention to the optimal treatment that the right-hand-column group gets.
Verma et al (2017)
Bikash Verma, Philippe Aftimos, Ahmad Awada, Jean-Pascal H. Machiels, Jason B. Brayer, David A Sallman, Tessa Kerre, Kunle Odunsi, Caroline Lonez, David Edward Gilham, Frederic Lehmann,
NKG2D-based CAR-T therapy in a Multinational Phase 1 Dose Escalation and Expansion Study Targeting Multiple Solid and Hematologic Tumor Types.
HBSS = Hank's Buffered Salt Solution, injected as a placebo
NSG mice = an inbred strain of severely immunodeficient laboratory mice
As expected, the untreated HBSS Group produced the worst results, and the NKR-2 Group produced the best, but not a complete cure, although if a complete cure had been sought, then a third and a fourth and a fifth NKR-2 infusion could have been given, but it was not, the reason perhaps being that the Dartmouth laboratory of Charles L Sentman tends to stick to a standard format in its different experiments so as to make the results from the different experiments more comparable to each other.
Demoulin (2017) Similarly Suggests|
That CAR-T NKR-2 Cures Pancreatic Cancer in Mice
Another experiment, also from the Dartmouth laboratory of Charles L Sentman, reinforces the notion that experiments are kept within a standard format so as to make their results more comparable — we note below that the bioluminescent photos were also taken weekly and also ended at Days=35 and also that the NKR-2 infusions were given on Days=12 and 19. The identical text occasionally legible against the black background within the photos in Verma (2017) and Demoulin (2017), and the identical background details in the respective sets of photos, invite the hypothesis that the images were produced by the same equipment.
The chief difference between Demoulin (2017) and Verma (2017) is the nature of the group presented in the middle column, but which difference does not concern us here, and the benefit of repeating HBSS and NKR-2 groups is that they provide replication, the absence of which leaves scientists greeting new results warily.
Demoulin et al (2017)
Benjamin Demoulin, W. James Cook, Joana Murad, David J Graber, Marie-Louise Sentman, Caroline Lonez, David E Gilham, Charles L Sentman, and Sophie Agaugue, Exploiting natural killer group 2D receptors for CAR T-cell therapy, Future Oncology, Epublished online, 14 June 2017.
Bold red font added to name of laboratory head.
Celyad's general conclusion
covering all of its murine-model research is that CAR-T NKR-2 is able to produce cures: "Celyad has generated breakthrough preclinical data in murine models, leading to 100% long-term survival".
Kottke (2011) and Boisgerault (2013)|
Cure Prostate Cancer By Vaccination
The press covered Kottke (2011) as follows:
The first cancer vaccine that works
Annalee Newitzs 20 Jun 2011
Cancer vaccines may come sooner than you think. And each vaccine will be tailor-made for a specific kind of cancer. This isn't just a theory anymore. It's been done.
A group of medical researchers in the U.K. and the U.S. have successfully cured prostate cancer in mice using a vaccine made partly from healthy human prostate DNA, delivered inside virus shells. This treatment could come to replace toxic chemotherapies, curing cancer with no painful side effects. [...]
The big question now is whether this therapy could work in humans. Clinical trials that would lead to using this therapy on humans could begin in two years.
FIRST CANCER VACCINE THAT WORKS
To be found in Kottke (2011), and in a later murine-model-prostate experiment also coming from the Richard Vile lab at the Mayo Clinic in Rochester MN, are non-Kaplan-Meier Overall Survival graphs containing 100% curves (suggestive of total cures) of the sort that in KAPLAN-MEIER had been presented only in an imaginary example:
Timothy Kottke, Fiona Errington, Jose Pulido, Feorillo Galivo, Jill Thompson, Phonphimon Wongthida, Rosa Maria Diaz, Heung Chong, Elizabeth Ilett, John Chester, Hardev Pandha, Kevin Harrington, Peter Selby, Alan Melcher, and Richard Vile, Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors, Nature Medicine, 2011, 17, 854-859.
There are possibly two 100% curves above, one underneath the other, one identified as ASEL, the other as ASEL-CD8. Bold red font added to name of laboratory head. Worth noting is that the above overall-survival graph is not Kaplan-Meier, and that curves are permitted to plunge to zero.
Nicolas Boisgerault, Timothy Kottke, Jose Pulido, Jill Thompson, Rosa Maria Diaz, Diana Rommelfanger-Konkol, Addie Embry, Dyana Saenz, Eric Poeschla, Hardev Pandha, Kevin Harrington, Alan Melcher, Peter Selby, and Richard Vile, Functional Cloning of Recurrence-specific Antigens Identifies Molecular Targets to Treat Tumor Relapse, Molecular Therapy, 2013, 21(8), 1507-1516.
The three asterisks signal a footnote, not reproduced here, which indicates that the probability of coming across such a curve separation by chance is P<0.001. Note that Timothy Kottke, first author of Kottke (2011) is second author of Boisgerault (2013). Bold red font added to name of laboratory head. Overall-survival graph is not Kaplan-Meier, and curves are permitted to plunge to zero.
HERE'S WHAT MURINE-MODEL RESEARCH CAN TEACH US
We need right now to make a guess at how much it might cost to run a bioluminescent-imaging experiment like the three described above.
The number of mice per experiment was either 12 or 15 or 20, and the number of days in the experiment was either 35 or 58, and the number of times each mouse was injected was either 2 or 3. To be paid for are the mice themselves, an allotment of individual cages in a rack of cages, food and cleaning, lab work in preparing the infusion, personnel to inject the mice and photograph them and write down numbers and analyze them, and of course pro rata use of the bioluminescent-imaging equipment.
Three prices per experiment are rattling around in my head at the moment, for a reason that will soon be made apparent — do they seem too low to you, or too high? The numbers are $24 thousand per experiment, or $86 thousand, or $61 thousand, no pairing with any particular experiment intended. These numbers seem high to me, but I'm going to assume that I do not appreciate how costly the use of the imaging equipment is, and also the lab work of preparing the infusion, and so will take these three dollar amounts as falling in the ball park of how much a bioluminescent-imaging murine-model experiment might cost.
Now I'd like to compare the above estimated cost of running a murine-model experiment to estimated costs of running human clinical trials, and here I can quote estimates cited by the U.S. Department of Health & Services, Office of the Assistant Secretary for Planning and Evaluation at ASPE: "$24 million, $86 million, and $61 million for Phases 1, 2, and 3, respectively"!
In other words, it might cost one thousand times as much to run a clinical trial as to run a lab experiment. And in still other words, for the price of running one clinical trial, it might be possible to run a thousand lab experiments instead.
And there are duration differences as well. The three bioluminiscent-imaging studies we are talking about took either one month or two months, whereas San Miguel (2013) stretched the San Miguel (2008) data to Months=78, so that one might say that it took 78 times as long as a one-month mouse experiment, or 39 times as long as a two-month mouse experiment.
And we have noted that it is possible to ask questions of animals that cannot be asked of humans — among them the supremely-import question of what happens when no treatment is administered?
And there is still another comparison that is very relevant to the present argument — and that is that the San Miguel (2008) trilogy was so totally devoid of scientific legitimacy that it proved exactly nothing, whereas every animal experiment leaves behind it another piece fitted into the jigsaw puzzle that is cancer.
And there is one final comparison that is relevant, and that is that mice suffer and die in lab experiments for the noble purpose that men and women and children will not suffer and die. In the case of bortezomib, and undoubtedly other cytotoxic drugs, men and women suffer and die in clinical trials for the ignoble purpose of producing infomercials.
The above argument lays out a path to an indispensable intermediate goal, and which is understanding cancer so well that it becomes a straightforward matter to give any cancer to any species of animal, and also to cure those same cancers in those same species quickly and painlessless and completely. When we are able to do this, and the five murine-model experiments above suggest that we are well on our way to doing it, then the remaining final step will be a small one compared to what has already been accomplished, and that is the final step of extrapolating this knowledge to curing humans of those same cancers, and curing humans as quickly and painlessly and completely as we have learned to cure animals.
A NEW STANDARD FOR CLINICAL TRIALS
The reason that today's cytotoxic chemotherapy clinical trials are unable to produce anything better than infomercials is that patients come to understand that the chemotheray triggers devastating adverse reactions, that the devastation may last not just for years but for life, and that the chemo may shorten that devastated life. It is these realizations that lead to all the laboratory malpractice that comes to invalidate clinical trials — as for example dosage reduction, confounding background therapy to treat adverse reactions, frequent non-random patient drop-outs destroying the pre-treatment equality of patient characteristics, and so on.
But if a new-standard clinical trial were able to target cancer cells so accurately that adverse reactions were diminished, and if the new-standard treatment was brief, and if it held out hope of a cure, then patients would have the strongest imaginable motivation to enroll in the clinical trial and stick with it to completion. Therefore, all that it would take to protect medicine from being drowned in today's infomercial tsunami is to limit clinical trials to treatments that can be expected to be humane and beneficial — and more concretely, is to permit only clinical trials that intend to replicate experiments that have already been performed on animals, and which animal experiments meet the requirements of being humane and beneficial, and which animal experiments include a NO-CHEMO control group, even though the parallel human clinical trial will be unable to.
The new standard for clinical trials centers around patients, say inducted into bortezomib treatment, knowing that they have the right to ask, and to receive an answer to, the question, "What happened to mice when they got the bortezomib treatment that you plan giving me, compared to mice receiving no chemotherapy at all?" Given that the clinical-trial sponsor — say Johnson&Johnson — can have earlier run the murine-model version at one one-thousandth the cost of the proposed human clinical trial, there can be no excuse for having failed to provide such a murine-model prerequisite to the clinical trial. To put it another way, patients need to be reassured that they have the right to ask pharmaceutical manufacturers and vendors why they expect humans to play the role of guinea pigs when real guinea pigs have never been asked to play that role.
A conceivable objection to the above plan is that it encourages dreaming of a utopia lying in the distant future, whereas existing clinical trials are oriented toward supplying today's cancer patients with whatever drugs it is realistically possible to manufacture today, rather than asking them to live with their cancers untreated while awaiting a miracle cure.
To this accusation of utopian dreaming, it is possible to proclaim the good news that utopia has already arrived. The name of that utopia is immunotherapy, and the most-promising package of immunotherapy being tested right now bears the title CAR-T NKR-2 that we have glimpsed above almost-curing pancreatic cancer in mice, and the package is signed Charles L Sentman.
LET "THINK" SERVE AS PROTOTYPE
It is widely repeated that to hope for "a cure for cancer" is naive because there is not just one kind of cancer, there are hundreds of different cancers, and each will require the discovery of its own unique cure.
But perhaps the naivete lies more on the side of those who fail to recognize that cancers may share a common thread which can be relied upon to find a cure applicable to all of them, although that single cure will need to be tweaked so as to more accurately target the particular cancer a patient happens to be carrying.
The argument for the latter view must have some merit, else European and American regulators would not both have approved Celyad's CAR-T NKR-2 THINK (from THerapeutic Immunotherapy with NKR-2) clinical trial which intends to aim T-cells at seven different cancers: the five solid cancers — ovarian, bladder, colorectal, pancreatic, and triple-negative breast — and the two hematological cancers — acute myeloid leukemia and multiple myeloma.
Perhaps an assault as stunning as attacking seven cancers in one clinical trial has never previously been attempted. At best, it may go down in history as having accomplished something close to finding a cure for cancer. But if it goes down in history for only beating two cancers out of the seven, or even one, it will still be a milestone deserving the gratitude of all mankind, for the following further reasons.
THINK expects not just the small amelioration of some cancer signs, at the cost of immense suffering, that is typically hoped for in clinical trials, but rather expects full cures, at the cost of small suffering.
And compared to typical cytotoxic chemotherapy, the duration of CAR-T NKR-2 THINK treatment is brief and therefore comparatively undisruptive of the patient's life, as is laid out in the calendar below. Starting at day minus 28 is the part where samples are taken of the patient's T-cells and the T-cells' ability to focus their attacks on the patient's cancer cells is improved, and so that they can later — on days D1, D15, and D29 — be infused back into the patient's blood stream, and which three infusions constitute the therapy. Everything after D29 is not therapy, it is monitoring what is happening inside the patient's body, at intervals which increase at first by days, then by three-month jumps, then by six-month jumps:
Also, as THINK employs no chemotherapy and no radiation, it expects none of the adverse reactions associated with these treatments. The adverse reaction of Cytokine Release Syndrome which has plagued other CAR-T trials has so far shown itself to be weak using NKR-2.
Although the THINK clinical trial is still only in its earliest stages, there seems to be no competing treatment which offers as much hope:
Celyad Reports Impressive Preliminary|
CAR-T Results in Solid Tumors
Clara Rodríguez Fernández on 19 June 2017
Celyad has announced no toxicity and stable disease in colorectal cancer patients after just 3 months of its first trial testing CAR-T in solid tumors.
After only 3 months of follow-up, Celyad already has positive results for its CAR-T NKR-2 therapy, which is designed to target 80% of tumors. Two of the three patients with metastatic cancer have achieved stable disease status. Both have colorectal cancer and their disease had been progressing even after undergoing at least two chemotherapy treatments each.
"Despite being dosed only at a tenth of the expected efficacious dose based on animal experiments, the results show a stabilization of the disease," said Christian Homsy, CEO of Celyad, in a statement. The third patient, with pancreatic cancer, is still in progression, and the company is now enrolling patients to test a higher dose.
With no toxicity found in any of the three patients and already showing efficacy, Celyad’s therapy is showing potential to surpass Novartis or Kite Pharma, which are running to be the first to put CAR-T on the market but have reported severe side effects and even deaths. Juno Therapeutics, which used to lead the pack, had to terminate its lead CAR-T program due to 5 patient deaths. However, it is still very early to determine whether Celyad will be able to maintain such promising results in higher doses and larger-scale trials.
Overall, then, what we see in the CAR-T NKR-2 THINK trial is the removal of all the obstacles that made it impossible to do valid research in San Miguel (2008) — the prolonged suffering leading to confounding background therapy and to patient dropout, and the patient hopelessness leading to more dropout and to confounding by alternative therapies, and the dropouts destroying the pre-treatment equality of patient characteristics while also necessitating reliance on misleading Kaplan-Meier graphs, and so on.
Therefore, to the hope that CAR-T NKR-2 will cure cancer can be joined the hope that it will also show how to run scientifically-respectable clinical trials from which valid conclusions can be drawn.
Explanation of how to participate in the THINK clinical trial can be had by clicking the rectangle:
ELABORATING THE RED BOX WARNING
Some jurisdications require that clinical trials comply with International Council for Harmonisation-Good Clinical Practice (ICH-GCP) standards, succinctly introduced in the following posters and quote. ICH elaborates to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Prior to 2015, ICH stood for International Conference on Harmonisation.
GUIDELINE FOR GOOD CLINICAL PRACTICE
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.
The sections from the ICH-GCP Guideline For Good Clinical Practice relevant at the moment are shown below, with lines of the highest relevance highlighted in yellow:
4.8 Informed Consent of Trial Subjects
4.8.10 Both the informed consent discussion and the written informed consent form
and any other written information to be provided to subjects should include explanations of the following: [...]
(m) That the subject's participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled. [...]
(p) That the subject or the subject's legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject's willingness to continue participation in the trial. [...]
5.4 Trial Design
5.4.1 The sponsor should utilize qualified individuals (e.g. biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs [Case Report Forms] and planning the analyses to analyzing and preparing interim and final clinical trial reports.
In view of the ICH-GCP information above, there may now be added further cautions to the earlier unofficial RED BOX WARNINGS at KAPLAN-MEIER redbox and TRILOGY redbox:
RED BOX WARNING
is not yet an
BLACK BOX WARNING,
but should be:
Patients in clinical trials should be aware that researchers sometimes need to be reminded of their obligation to protect patient health and safety by complying with ICH-GCP (International Council for Harmonisation-Good Clinical Practice) guidelines.
For example, researchers have been obligated ever since 2015 to inform all Bortezomib patients of the Katz (2015) discovery that Bortezomib weakens the ability of mice to fight off multiple myeloma. Why have researchers been so obligated? Because that Katz information "may be relevant to the subject's willingness to continue participation in the trial", as is spelled out above in ICH-GCP ¶4.8.10(p). Because, more specifically, that Katz information would open up to patients the option of discontinuing participation, out of fear that bortezomib might cut their lives short the way it had cut Katz's mice lives short.
For another example, ICH-GCP ¶5.4.1 above has been obligating researchers from much farther back than 2015 to acquire competence in designing research and interpreting its results, and yet this obligation has also been falling on deaf ears, as has been demonstrated by researchers breaking every rule in the book during the San Miguel (2008) trilogy. This lapse of a fundamental obligation is not a recent discovery, it is common knowledge — common knowledge that medical training neglects education in scientific method, leaving most doctors incompetent in designing and interpreting research:
Many health care professionals do not receive training in research methods (Bonham, Califf, Gallin, & Lauer, 2011) and have difficulty understanding research results and therefore applying them (Kramer, Smith, & Califf, 2012) [...]. [...]
A related issue is the failure of academic medical curricula at the graduate and undergraduate levels to encourage fundamental principles of clinical research. Even training designed for investigators neglects research principles in favor of an emphasis on strict compliance with standard operating procedures (Kramer, Smith, & Califf, 2012). Those studying to be physicians are not adequately trained in advanced statistical methods to interpret clinical trial results (even at the level at which they are reported in medical journals), impairing their ability to use such results to inform their clinical care and practice evidence-based medicine (Kramer, Smith, & Califf, 2012; Horton & Switzer, 2005). For example, in a survey of 367 residents from 11 programs, only 37.4 percent knew how to interpret an adjusted odds ratio from a multivariate regression analysis. Seventy-five percent of survey respondents said they did not understand all the statistics they saw in journal articles, but the vast majority felt it was important to be familiar with the concepts in order to understand the literature (Kramer, Smith, & Califf, 2012; Windish, Huot, & Green, 2007).
The two obligations above are not ones that have been neglected only in the past.
The obligation to inform Bortezomib patients of Katz (2015) is an obligation that continues to be ignored today. That Katz (2015) is the only publication in existence capable of lowering "the subject's willingness to continue participation in the trial" is implausible — there are undoubtedly others, and these too it is obligatory to bring to the attention of patients in clinical trials. The ICH-GCP ¶4.8.10(p) guideline is being ignored. Patients are not being warned of the dangers they are being exposed to, for which failure they continue to pay with their health and with their lives.
And ICH-GCP ¶5.4.1 also continues to be ignored. Most medical practitioners can't distinguish good research from bad, and no program to bring them up to par is being announced. ▢