BRIGHT FUTURE FOR J&J DARZALEX?
by Semmel Weis
First published 24Oct2017
Last edited 20Sep2018 04:03pm
GOODBYE BORTEZOMIB, HELLO DARZALEX
As has been noted earlier, but is repeated here to introduce the next topic of discussion — even before news of Bortezomib (=Velcade) invalidity has had much chance to spread, its Johnson & Johnson revenue is being predicted to "nosedive" from $1.2 billion in 2016 to a measly (by big pharma standards) $150 million by 2023.
Not to worry about Johnson & Johnson's financial well-being, though! J&J has a new multiple myeloma drug already in the works — Darzalex (=Daratumumab) — which is expected to more than compensate for the decline of Velcade. Darzalex revenue is calculated to rise from its observed $572 million in 2016 to an expected more than $4 billion in 2023, and might come also with a "peak sales potential" of $7 billion, which general impression is all that is essential for the reader to extract from the box quote below:
Given that Johnson & Johnson has had many years to improve its fatally-defective Bortezomib-promoting San Miguel (2008) research methodology, it may be reasonable to expect that its recent research promoting Darzalex is of upgraded quality such that the safety and efficacy of Darzalex rest on a surer foundation.
WHAT THE WORLD THINKS OF CASTOR AND POLLUX
CASTOR AND POLLUX (in addition to being twin brothers in Greek and Roman mythology, said to have won immortality by being transformed into the constellation GEMINI) are the names of two Johnson & Johnson clinical trials which are frequently cited in the promotion of Darzalex:
CASTOR: Antonio Palumbo et al (2016), Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma, New England Journal Of Medicine, 25Aug2016, 375, 754-766.
NEJM CASTOR ARTICLE
NEJM CASTOR SUPPLEMENTARY APPENDIX
NEJM CASTOR PROTOCOL
ICMJE CASTOR DISCLOSURE FORMS
POLLUX: Meletios Dimopoulos et al (2016), Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma, New England Journal Of Medicine, 06Oct2016, 375, 1319-1331.
NEJM POLLUX ARTICLE
NEJM POLLUX SUPPLEMENTARY APPENDIX
NEJM POLLUX PROTOCOL
ICMJE POLLUX DISCLOSURE FORMS
Below is a sample of ten standing ovations applauding Darzalex and its CASTOR/POLLUX foundations. The widespread enthusiasm which greets Darzalex is all that need be extracted from these examples.
1. "DARATUMUMAB IS 'KNOCKING IT OUT OF THE PARK' FOR ME!"
2. "YOU HAVE A BREAKTHROUGH"
DARZALEX™: The Multiple Myeloma Drug That Could
By Meghan Rabbitt March 15, 2016
Johnson & Johnson
Ahmadi and his team
[...] "I’ll never forget what this esteemed doctor said to me after looking at the clinical trial results," says Ahmadi, 43, now the Vice President of Experimental Medicine and Early Development for Oncology at Janssen. "He said, ‘You don't have a drug — you have a breakthrough.’ It was so motivating."
It wasn’t the first and wouldn’t be the last breakthrough moment for Ahmadi: The Food and Drug Administration (FDA) would ultimately grant Janssen a Breakthrough Therapy Designation for Darzalex™ and approve it for patient use 18 months ahead of the company’s initial timeline.
Breakthrough Therapy Designation is significant in the world of drug research and development: Medications that receive this distinction are prioritized within the FDA to help get them to patients more quickly.
"I vividly remember one story of a patient in our Phase 2 study who had tried everything, but the disease was still progressing," recalls Ahmadi. "When he enrolled in the study, he thought he was simply contributing to research before he died. Instead, his doctor called me and said that his patient was responding well to Darzalex™." [...]
3. "IS WELL ON ITS WAY TO BLOCKBUSTER SALES STATUS"
4. "RESULTS ARE UNPRECEDENTED"
New cancer drugs target deadliest forms of the disease
Pharma groups unveil encouraging research that fuels hopes for patients who have run out of options
by David Crow in Chicago June 5, 2016
[...] About 35,000 doctors and scientists gathered in Chicago at the weekend for the annual meeting of the American Society of Clinical Oncology (Asco), where the results of more than 5,000 clinical trials were published. [...]
"These results are unprecedented in this cancer," said Dr Antonio Palumbo, an oncologist at the University of Torino in Italy, who led the study. The Darzalex combination would soon become the most common medicine given to multiple myeloma sufferers, he predicted. [...]
5. "HAILED DARATUMUMAB AS A GAME CHANGER"
Johnson & Johnson's Darzalex Is An Emerging Threat To The Primacy Of Celgene's Revlimid
Intrepid Investor 29 Aug 2017
[...] Darzalex is Johnson & Johnson's fastest growing drug and sales are accelerating. [...]
If Darzalex daratumumab is approved in combination with bortezomib, melphalan, and prednisone as front line, it will be a direct threat to Revlimid maker Celgene (CELG). In the most recent quarter, the $460-a-pill Revlimid accounted for $2,034 of $3,256 (millions) total revenue. Even a modest encroachment by Darzalex will be very costly to Celgene given that degree of dependency on Revlimid.
Experts in the field have already hailed daratumumab as a game changer.
A NEJM editorial (Rajkumar & Kyle, 2016) concerning the POLLUX and CASTOR trials refers to results with the anti-CD38 monoclonal antibody as "unprecedented" and "a singular breakthrough in the treatment of myeloma."
In the POLLUX trial (Dimopoulos, 2016) of previously treated patients, daratumumab provided an overall 12-month survival advantage (92.1% vs 86.8%) to patients also treated with Revlimid and dexamethasone. The absolute PFS achieved in that trial appeared superior to that achieved in CASTOR in which daratumumab, bortezomib, and dexamethasone were used.
Six weeks after publication of the POLLUX and CASTOR trials the FDA approved Darzalex as 2nd line therapy of myeloma on the condition that it be given with lenalidomide (Revlimid) and dexamethasone. [...]
[bold emphasis added to CASTOR and POLLUX]
6. "CANADIANS HAVE GOOD REASON FOR HOPE"
Janssen Inc. Receives Health Canada Approval of DARZALEX® (daratumumab) by Priority Review for Patients with Multiple Myeloma Who Have Had At Least One Prior Therapy
DARZALEX® combination therapy significantly improved progression-free survival (PFS) compared to standard of care regimens alone
TORONTO, April 17, 2017 /CNW/ — Janssen Inc. announced today that Health Canada has approved DARZALEX® (daratumumab), in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. Due to the high unmet medical need for multiple myeloma patients, DARZALEX® was granted a Priority Review by Health Canada for this submission.
[...] "Canadians living with multiple myeloma have had good reason for hope in recent years with the Health Canada approvals of new treatments like DARZALEX®," says Aldo Del Col, Co-Founder and Chairman, Myeloma Canada. [...]
Data from two Phase 3 studies supported this new approval. They include the open-label, randomized clinical studies POLLUX (MMY3003) and CASTOR (MMY3004). [...]
[bold emphasis added to CASTOR and POLLUX]
7. "EU EXPANDS USE"
EU expands use of Janssen’s Darzalex
by Selina McKee 02 May 2017
[...] The decision to expand the drug’s approval was based on findings of the Phase III POLLUX and CASTOR trials, which showed that the addition of Darzalex significantly reduced the risk of disease progression or death — by 63 percent and 61 percent, respectively — when combined with standard of care regimens. [...]
[bold emphasis added to CASTOR and POLLUX]
8. "GREAT NEWS FOR MYELOMA PATIENTS IN SCOTLAND"
Patients in Scotland first to get new blood cancer drug daratumumab on NHS
Helen McArdle 09 Oct 2017
AN INNOVATIVE new drug for the treatment of a complex blood cancer has been approved for use on the NHS in Scotland. [...]
Rosemarie Finley, chief executive of the organisation said: "This is great news for myeloma patients in Scotland and their families.
"Daratumumab is an exciting and innovative new treatment which has been shown to have a very beneficial effect on length of remission in patients who respond." [...]
9. "TRULY ASTOUNDING RESULTS"
Janssen's Darzalex combo should become new standard of care in multiple myeloma, say scientists
The Pharma Letter 05 Jun 2016
PharmaLetter on YouTube
Peter Lebowitz, global head of oncology at Janssen, talks to TPL about the "truly astounding" results from a Phase III trial of Darzalex (daratumumab) in combination with Velcade (bortezomib) and dexamethasone, which demonstrated a 61% reduction in the risk of disease progression or death.
This has led scientists to say the combination therapy should become a new standard of care for relapsed or refractory multiple myeloma patients.
10. "LEVELS OF CANCER REDUCED FROM NEAR 300 TO JUST 18"
Blood cancer drug hailed a "game changer"
Grant McArthur, Health editor, Herald Sun 29 Oct 2017
Denis Livis, with wife Lisa, children Jason, 27, and Thaleia, 25, and dog Sebby, has seen his cancer levels plummet. Picture: Yuri Kouzmin
[...] After being diagnosed with advanced multiple myeloma a year ago, Denis Livis has seen chemotherapy and high-dose chemotherapy fail to affect the cancer, before a stem cell transplant and thalidomide treatment resulted in a partial response. Five weeks ago, he got Darzalex on a compassionate access scheme, and saw levels of cancer reduced from reading near 300 to just 18.
"I am nearly myeloma free," he said. "It is good news. It has taken a year, but I am happy to be here a year later with nearly getting the myeloma under control." [...]
THAT'S WHAT THE WORLD THINKS OF CASTOR AND POLLUX,|
BUT WHAT DO SCIENTISTS THINK?
THE FIRST THING THE SCIENTIST ASKS IS WHETHER THE AUTHORS ARE SCIENTISTS OR SALES REPS
It is immediately noticed that both CASTOR and POLLUX were funded by Janssen, which is wholly owned by Johnson & Johnson, and to which corporation the outcomes of the clinical trials make a difference of billions of dollars.
Turning next to look into Conflicts of Interest, there are none better to begin with than those of the lead authors, who also happen to be the designated "corresponding authors", Antonio Palumbo and Meletios Dimopoulos, and who acknowledge receiving payments from Pharmaceutical companies, including from Janssen:
"This study was funded by Janssen"
"Supported by Janssen Research and Development"
Address reprint requests to Dr. Palumbo at the Department of Hematology, University of Turin, Via Genova 3, 10126, Turin, Italy,
Meletios Eletios Athanasios Dimopoulos
Address reprint requests to Dr. Dimopoulos at the National and Kapodistrian University of Athens, School of Medicine, Alexandra Hospital, 80 Vas. Sofias, Athens 11528, Greece,
CASTOR-Palumbo Disclosure of 26-April-2016
"Dr. Palumbo reports grant support from Janssen during the conduct of the study, and personal fees and other support from Janssen-Cilag, Genmab, and Takeda outside the submitted work."
POLLUX-Dimopoulos Disclosure of 22-June-2016
"Dr. Dimopoulos reports grant support and personal fees from Janssen during the conduct of the study; grant support and personal fees from Janssen, and personal fees from Celgene, Amgen, and Novartis outside the submitted work."
The natural impulse after reading the potential conflicts of the 2 lead authors is to continue reading through the 41 other authors, for the sake of thoroughness and in the hope of discovering some pattern. However, the impulse to continue reading ICMJE disclosures is extinguished upon reading the following article and pondering its implications:
Big Pharma assailed for|
lack of transparency over payments
Critics say voluntary declaration of millions paid to physicians,
organizations doesn’t go far enough
KELLY GRANT HEALTH REPORTER 21 Jun 2017
Globe and Mail
Ten of Canada’s largest pharmaceutical companies have revealed that together they spent at least $48.3-million on payments to physicians and health-care organizations last year, a voluntary disclosure that critics of Big Pharma say falls well short of genuine transparency.
The figures provided a peek into how drug makers compensate this country’s physicians for consulting, delivering speeches, sitting on advisory boards and travelling to international medical conferences.
But the companies did not name any of the doctors, nor did they reveal the total number of physicians they paid or the amounts they provided to doctors for running clinical trials.
Even though the disclosures had been planned for two years, only four of the 10 companies provided figures for all of 2016.
One provided information covering just three months.
The minimal disclosure shows the federal government needs to step in and force the pharmaceutical industry’s hand, according to the Toronto doctor behind Open Pharma, a pro-transparency campaign.
"Allowing pharma to go with self-regulation or their own voluntary measures has left us really far behind," said Andrew Boozary, a resident physician at St. Michael’s Hospital.
"I can’t see anybody really celebrating this as a progressive leap forward." [...]
The drug makers released totals of their spending in three categories: Payments to healthcare providers for services such as speaking and consulting; funding to health-care organizations such as hospitals; and funding to health-care providers to support their travel to international medical meetings and conferences.
Only 10 of the 45 members of Innovative Medicines took part in the voluntary effort. Each posted figures to its own website, and not always in an easy place to find. [...]
The following three indented and smaller-font paragraphs explain how I arrived at the table below. If you are not interested at the moment in checking my arithmetic, you can just read the two bold-font sentences, then pass on to the table which lays out four scenarios of how Big Pharma might distribute to 937,857 active Canadian and American doctors the USD$2,583,555,000 (2.58 billion, we could say) that the above article implies Big Pharma hands out annually to the medical community.
To get a more accurate estimate of annual Big Pharma payouts, multiply the Eli Lilly figure of 1.94 by 4, and the Abbvie, Amgen, Novartis, Bristol-Myers Squibb, and Gilead figures by 2. SUM the new figures. I get SUM=74.46. As only 10/45 members of Innovative Medicines contributed data, get an estimate of total spending for ALL 45 members by multiplying SUM by 4.5. I get ALL=335.07. No idea of how many Big Pharmas have not been included in the Globe and Mail story because of their not being members of Innovative Medicines, so let that issue go for now. To get an idea of what the USA total spending might be, multiply ALL by the population of the United States (326,105,000) divided by the population of Canada (36,701,900): USA = 335.07 * 326,105,000 / 36,701,900 = 2,977.18. To get total payments for Canada and USA, add ALL + USA: 335.07 + 2,977.18 = 3,312.25. As all amounts in this paragraph have been in millions of Canadian dollars, move the decimal place over six places to get CAD$3,312,250,000, and which at the moment (0.78 exchange rate on 29Oct2017) equals USD$2,583,555,000.
If there are 854,698 active doctors in the USA and 83,159 active doctors in Canada, that's a total of 937,857 active doctors in both countries, and to get average Big Pharma payment per doctor: USD$2,583,555,000 / 937,857doctors = USD$2,754.74 per doctor. However, doctors don't all receive the same amount from Big Pharma, and most doctors possibly receive nothing, so we may note that if the same Big Pharma money was spread over only one doctor out of ten, then 93,786 doctors would each get USD$27,547.40, and if spread over only one doctor out of a hundred, then 9,379 doctors would each get USD$275,461.67. Highly motivated by an annual payment of over a quarter of a million US dollars, a force of 9,379 sales representatives — sporting MDs and spread over Anglo North America — can have a large impact on drug attitudes and drug sales.
Moving just a bit farther along the same scale, one may imagine that if Big Pharma distributed its pie only among the ten stars of pharmaceutical promotion, perhaps the most frequently-quoted heads of the ten most prestigious clinics in the US and Canada, then Big Pharma annual payouts to each of these ten idols of pharmaceutical sales would be USD$258 million.
|SUBSET DOCTORS PAID
||NUMBER DOCTORS PAID
||PAY PER DOCTOR
|ONE DOCTOR IN TEN
|ONE DOCTOR IN A HUNDRED
|TEN CELEBRITY DOCTORS
Of course many of my off-the-cuff assumptions above need to be improved and many of my quickie computations need to be refined, but it can be doubted that any revised estimates would alter the conclusion that I am making — that the CASTOR/POLLUX ICMJE Disclosures of Potential Conflicts of Interest referred to above play the role more of smoke screen than of disclosure, because they inform us merely that some payment greater than zero has changed hands, which means nothing, whereas it is what we are not being told that means everything, and what we are not told is whether that payment is USD$258 or USD$258 thousand or USD$258 million.
If Big Pharma was selling drugs that really worked the way patients are led to believe they work, then Big Pharma would not have to make such extravagant sales-force payments, and would not even have to advertise, and could dedicate its resources to performing scientific experiments instead of producing infomercials.
THE SECOND THING THE SCIENTIST LOOKS FOR IS AN ANIMAL-MODEL PRECEDENT
The scientist does not dare to perform experiments on humans unless his treatments have first been shown to bring good to animals, and to do them no harm, so that the first thing he will want to see is the results obtained with animals, say rats, that have endured the same experiment that was later conducted on humans.
Doing anything to humans that has never yet been done to animals will strike the scientist as unethical and immoral. As the rat study which most closely corresponds to a proposed human study might cost one-thousandth as much to perform, and might be conducted in one-fiftieth the time, the pharmaceutical sponsor has no excuse for failing to conduct such a prerequisite experiment, and to submit the results to regulatory authorities as the chief exhibit in the application for clearance to conduct the human version of the study.
As the animal equivalent of the proposed human clinical trial would be able to include the zero-chemotherapy control group that is understandably absent from VISTA/CASTOR/POLLUX, that zero-chemotherapy control group would be able to throw light on the possibility that all the chemotherapy groups tested were in fact shortening life.
WHAT THE SCIENTIST LEARNS JUST FROM EYEBALLING THE CASTOR-POLLUX OVERALL-SURVIVAL GRAPHS
The next-most-important thing that the scientist turns his attention to is the Overall-Survival graphs, like the Ozaki (2015) one on the right, and which has several important features, the one of immediate interest being that it follows survival to Months-After-Initial-Therapy = 160, and which happens to equal 13 years and 4 months.
It takes no more than a quick glance at the CASTOR/POLLUX Overall Survival graphs below to find eight disappointments:
(1) SEVERE TRUNCATION OF THE CASTOR/POLLUX DOMAINS
Two thin vertical lines added to the Ozaki (2015) graph show how much information would have been discarded if the graph had extended to only Months=15 or 21. And yet the CASTOR graph further below does extend only to Months=15, and the POLLUX graph beside it only to Months=21.
Palumbo (2016) happens to not only apologize for failing to provide data on longer-term Overall Survival, but also happens to confess that his methodology renders longer-term Overall Survival data unusable because the farther right one goes in the graph, the greater becomes the proportion of Control-Group subjects who have begun to be dosed with Daratumumab, so that the assumption that the Control-Group curve represents subjects who got no Daratumumab becomes increasingly untenable:
[B]ecause of the relatively short follow-up period, we could not assess whether the addition of daratumumab to bortezomib and dexamethasone confers an overall suvival benefit. The final analysis of overall survival [to be conducted some time in the future] will be confounded by the treatment effects of daratumumab in the control group because patients in the control group were allowed to receive daratumumab after the interim analysis was completed.
Above, then, we read a Palumbo (2016) admission that any future Overall-Survival analysis will be confounded in the sense that the two curves in the graph will no longer differ in the intended single respect only (the Experimental Group getting Daratumumab and the Control Group none) — but rather, that the Control Group will now be transformed from an Intended-Zero-Daratumumab Group into an Intended-Zero-Daratumumab-At-First-But-Some-Subjects-Getting-Lots-Later-On Group. And yet, after affirming this confounding of any longer-term follow-up, Palumbo nevertheless goes on to promise just such a longer-term follow-up, with the expectation that out of mishmash will be extracted clarity:
Long-term follow-up is continuing [to be worked on so as to be able eventually] to better characterize the effect of daratumumab on these longer-term clinical end points.
We must at this point recognize the enormity of the error that Palumbo (2016) proposes to commit in his longer-term follow-up, which is to fail to recognize that in addition to many of the Control-Group subjects opting down the road to begin Daratumumab therapy, there will be many subjects from both groups who will wander off into any of a vast array of alternative therapies, and sometimes into several alternative therapies, either simultaneously or sequentially.
A scientist hearing the Palumbo (2016) proposal for "long-term follow-up" will perceive it as wading into a scene of total chaos from which no conclusions can be extracted, and which in particular will be unable to cast any light on the effect of Daratumumab on longer-term Overall Survival.
It is particularly disappointing that Johnson & Johnson should publish data having such brief domains as Months=15 or 21 when the hypothesis today circulates that chemotherapy sometimes weakens short-term measures of cancer symptoms while failing to extend Overall Survival, or even while shortening Overall Survival.
(2) VISTA/CASTOR/POLLUX SEEM TO BE PROTECTED FROM TERMINAL PLUNGES
It will be noted in the Ozaki (2015) graph above that the green curve initially shows the highest Overall Survival, but at approximately Months=132 plunges to zero, a phenomenon which I have been calling a Terminal Plunge, and which is a common occurrence in Kaplan-Meier graphs — common, that is, so long as the curves are not being tampered with — and whose appearance can occur much earlier than Months=132, and which in its plunge toward zero can cut across other curves in the graph, as the green curve does. If a Terminal Plunge like this green one happened to appear early in the curve representing whatever drug was being promoted, say in the Bortezomib Curve in VISTA, or in the Daratumumab Curve in either CASTOR or POLLUX, it would leave the very vivid and negative impression that the Bortezomib or Daratumumab killed all subjects suddenly and prematurely, and which would sink the chances of getting those drugs approved. And perhaps Terminal Plunges to zero are unwelcome in the Control Group curve as well, because they might suggest that the two accompanying drugs kill all subjects suddenly and prematurely.
Perhaps that explains why a Terminal Plunge to zero made no appearance either in the Johnson & Johnson clinical trial that we scrutinized earlier, namely VISTA-San Miguel(2008), or the two we are scrutinizing now, namely CASTOR-Palumbo(2016) and POLLUX-Dimopoulos(2016).
The expedient which enables researchers to keep their graphs free of Terminal Plunges consists of merely discontinuing the clinical trial before the longest-remaining subject dies, as is described at
(3) ASKING ONLY A SINGLE QUESTION TYPIFIES INFOMERCIALS
Only two curves in an Overall Survival graph means only two groups were run, and only one question answered, which typifies infomercials which aim not to deepen understanding, but only to justify the "this drug helps" conclusion needed to win regulatory approval. However, when neither group is a zero-drug group, it is impossible to tell whether one or both of the conditions tested shorten life compared to taking no chemotherapy drugs at all.
In contrast, scientists trying to understand a phenomenon have scores of questions they want answered, and so they try to answer several within each experiment, which they are able to do by running several groups per experiment, and therefore drawing several curves per graph, most usually including that most interesting of all comparison groups — the zero-drug group.
True that sometimes two curves per graph is perfectly appropriate, or even one, but it is nevertheless the case that the most important graph in each of VISTA/CASTOR/POLLUX is the Overall Survival graph, and which three Overall-Survival graphs always show just two curves, whereas in the eight bioluminescence-imaging rat experiments examined so far on semmel-weis.org, two groups per experiment has been a rarity:
Boisgerault(2013)=2, Demoulin(2017)=3, Katz(2015)=3, Verma(2017)=3, Kottke(2011)=4, Sherbenou(2016)Figure3=5, Sherbenou(2016)Figure4=6, Xia(2017)=8.
(4) THE NUMBERS UNDERNEATH THE CASTOR/POLLUX GRAPHS ARE CRYPTICALLY LABELLED
"No. at risk" is likely to be misunderstood. The more accurate and clear label is "Number of subjects remaining in the experiment", or more briefly "No. subjects remaining". Also, as in both graphs the Daratumumab Group curve lies above the Control Group curve, readers would find it helpful to have the Daratumumab Group "No. at risk" numbers also lying above the Control Group numbers, which is the opposite of what is done in CASTOR/POLLUX.
(5) THE CASTOR/POLLUX INTENTION-TO-TREAT (ITT) PHILOSPHY IS INDEFENSIBLE
We are reminded in the POLLUX graph above that Johnson & Johnson subscribes to an "intent-to-treat" philosophy whereby data from all subjects is analyzed as if the subjects had all been treated as the researchers had planned to treat them before the study began, even if it later comes to light that they have been treated differently:
For example, [...] a patient may be randomized to receive treatment A but erroneously receive treatment B, or never receive any treatment, or not adhere to treatment A. In all of these situations, the patient would be included in group A when comparing treatment outcomes using an ITT analysis. Eliminating study participants who were randomized but not treated or moving participants between treatment groups according to the treatment they received would violate the ITT principle.
Detry, Michelle A., and Lewis, Roger J.
The Intention-to-Treat Principle: How to Assess the True Effect of Choosing a Medical Treatment,
Journal of the American Medical Association, 2014, 312(1), 85-86.
The Detry (2014) quote immediately above is not an exaggeration, or a reference to hypothetical cases too extreme to be found in real clinical trials. Both CASTOR-Palumbo and POLLUX-Dimopoulos are happy to consider large numbers of their subjects as life-long card-carrying members of whatever group they have been assigned to, even when the subjects have discontinued all treatment required of their group, whether it be the three drugs in the Daratumumab Group or the two drugs in the Control Group, and no matter how early in their participation that discontinuation occurred, and even when the subjects have declined all treatment before receiving any, and even when they switched groups, as by deciding to drop Daratumumab but not the other two drugs (thus, in effect, placing themselves into the Control Group), or as by picking up Daratumumab when their longer-term survival as Control-Group subjects was still being tracked (thus, in effect, placing themselves into the Daratumumab Group).
The problem created by treatment which destroys quality of life while maybe extending it a little is massive subject non-cooperation and discontinuation which ruins the research, depriving it of its power to confirm the safety and efficacy of the study treatment. Johnson & Johnson's ITT answer to this problem is to pretend that nothing bad is happening, and to draw conclusions as if the validity of all conclusions had not been lost.
Of course, the only valid resolution of this problem is to offer subjects clinical trials with less pain and more gain, as perhaps is beginning to happen in Celyad's CAR-T NKR-2 THINK clinical trial, where subject alienation and defection can be expected to be low.
(6) KAPLAN-MEIER CURVES MISLEAD
The VISTA/CASTOR/POLLUX Overall-Survival graphs are all Kaplan-Meier, whose inflation of survival probability increases with the number of subjects fled/shed, which is to say, inflation of survival increases as one moves from left to right in the graph. This inflation is immediately and glaringly evident — as for example in the CASTOR graph above (follow the vertical and horizontal orange arrows), the Daratumumab-Group curve at Months=15 points to 81% subjects surviving, which multipled by the number of subjects starting out in that group at Months=0, which can be seen to be 251, invites us to believe that 0.81*251 = 203 subjects have survived. However, the "No. at risk" numbers underneath the graph tell quite another story — that at Months=15, the number of subjects still in the Daratumumab Group is 0. In other words, by Months=15, every last one of the 251 subjects who started out in the Daratumumab Group is either dead or fled or shed. The two numbers whose incongruity needs to be appreciated are the 203 and 0 pointed to by the double-headed and dashed orange arrow.
To put it plainly:
Despite the Kaplan-Meier claim of 81% survival at Months=15, no CASTOR researcher has ever laid eyes on even a single subject who has survived 15 months of Daratumumab treatment. More generally, to refer to Kaplan-Meier survivors is to refer to incorporeal phantoms who can't be pointed to or named because they are only conjectured, but not observed, to dwell among subjects whom the researcher no longer tracks because they have been "censored" out of the clinical trial.
Same goes for the POLLUX graph on the right above, whose Daratumumab curve shows (follow the vertical and horizontal orange arrows) approximately 83% of the initial 286 Daratumumab subjects surviving at approximately Months=21, which suggests that 0.83*286 = 237 living subjects should have been counted and their names recorded by the POLLUX research staff at Months=21. However, the "No. at risk" 0 printed underneath Months=21 in the Daratumumab-group row of numbers informs us that no POLLUX researcher has ever seen any Daratumumab subject who survived to Months=21. Here too, the two numbers needing to be compared are marked by the double-headed and dashed orange arrow.
And the same incongruity leaps out at the reader from the Control-Group curves as well, although that reasoning has not been traced in orange.
A very modest first step toward making Kaplan-Meier curves less deceptive would be to replace the confusing and misleading "No. at risk" with "No. patients remaining" at the locations shown below. A bolder second step would be to plot within the graph the Patients-Remaining numbers conventionally only printed underneath the graph, as also has been done below, which added curves, being counts of real subjects, constitute scientific observations, whereas the Kaplan-Meier curves are counts of real subjects to which have been added guesses of the number who might still be alive among the censored subjects whom the researchers have stopped monitoring.
What readers of such upgraded graphs should be told is that the true number of subjects still alive could lie anywhere between the original way-up-high Kaplan-Meier curves and the added way-down-low Patients-Remaining curves. If every one of the censored subjects dies right after being censored, then it is the Patients-Remaining curves that describe reality.
(7) THE DRAWN CURVES ARE OBSCURED BY PILING CENSORED MARKS ON THEM
The filled triangles piled onto the Daratumumab-Group curve in each graph, and the unfilled circles similarly piled onto the Control-Group curve, mark the occasions of subjects exiting a study, as by withdrawing, or for any reason being lost to follow-up — subjects whom I have been calling the fled and the shed, and who in Kaplan-Meier discourse are called "censored", an unfortunate choice of words as the meaning intended is "lost to the experiment for any reason" and not "selected for suppression". Avoiding misleading labels like "censored" and "No. at risk" would remove obstacles to the layman being able to understand medical writing.
This fled/shed information would be of great value had it been presented numerically, or at least graphed precisely. Piling markers onto the curves, in contrast, not only obscures the precise location of each buried curve, but also makes the markers impossible to count. In the literature presenting Kaplan-Meier graphs that I have begun to read, I have never yet seen such markers referred to in support of any conclusion, which invites the judgment that they are too crudely heaped to be informative. That being the case, it is little wonder that some authors omit them.
(8) DOES JOHNSON & JOHNSON IGNORE AN IMPORTANT SCIENTIFIC OBSERVATION FOR COMMERCIAL REASONS?
Given that Johnson & Johnson breaks every rule in the scientific-methodology textbook in its CASTOR/POLLUX infomercials, and on the supposition that every violation has as its purpose making Darzalex look like a God-sent miracle for multiple myeloma sufferers, it is astonishing that the results Johnson & Johnson ends up publishing are so unimpressive.
That is, comparing the "Kaplan-Meier Guesses" curves in the CASTOR graph on the left above, I find the difference between Daratumumab and Control to be small and unconvincing, and likely to disappear or even be reversed if the research were replicated with all its methodological errors corrected. Same in the POLLUX graph on the right, whose Kaplan-Meier Control Group demi-plunge ("demi" because only half-way to zero) should not be taken as opening up an awesome difference between curves — that demi-plunge is a representation of two subjects remaining in the Control Group, and one of them dying, which is why the curve plunges half-way to zero. If the researchers waited for the last Control-Group subject to die too, the Control-Group curve would plunge all the way to zero, in what I have been calling a Terminal Plunge — but the researchers want to avoid showing any curves reaching zero, and it is possible to imagine that as this last subject looks like he/she might not last much longer, they decide to "censor" him/her, "shed" him/her in my terminology. That act of censorship is represented by the unfilled circle at the end of the Control-Group curve. Notice that the Control-Group curve does not extend as far to the right as does the Daratumumab-Group curve, perhaps because checking in on this one remaining patient a month or two later might have found him/her deceased, which would have required the Control-Group curve to be drawn plunged all the way down to zero.
The CASTOR/POLLUX authors do not graph, or otherwise rely on, the Patients Remaining data, but as we have plotted them, we are able to see that the Daratumumab and Control curves within each study mainly overlap and intertwine. The thin superiority that Daratumumab occasionally enjoys falls short of "game-changing".
In short, if CASTOR/POLLUX are demonstrating a Daratumumab effect, it is a weak effect, and it bears repeating that research advances medical science more, and alleviates suffering sooner, when, given a choice, it studies strong effects before weak ones, and yet CASTOR/POLLUX claim for Daratumumab only a weak effect. But where's the choice — the choice between studying a weak effect or a strong one? Why it's visible in the two graphs above. And it's clarified in the CASTOR+POLLUX GRAPH below.
The CASTOR+POLLUX GRAPH restricts attention to what has been actually observed (the Patients-Remaining Observations) and omits what has been only estimated (the Kaplan-Meir Guesses), and shouts very loudly the conclusion that Daratumumab had no effect capable of eliciting applause or encouraging hope of billions of dollars in revenue — whereas which infomercial the subjects were in, whether CASTOR or POLLUX, did have a stunning and utterly convincing effect, an effect calling for no statistical test to vouch for its significance. The CASTOR/POLLUX effect was that CASTOR patients abandoned their study sooner, and if their chief reason for dropping out was their own sharply-deteriorating health, then dropping out could be viewed as a signal of impending death. The CASTOR+POLLUX GRAPH below, then, could be interpreted as supporting the conclusion that Bortezomib shortens life. So, that's the big effect more worth studying, and glaringly obvious in Johnson & Johnson's own data:
Evidence has been presented several times on semmel-weis.org that in certain circumstances, Bortezomib does seem to shorten life. The CASTOR+POLLUX GRAPH reinforces this feeling, showing as it does that CASTOR subjects got BORTEZOMIB and witnessed subject loss early, and POLLUX subjects got LENALIDOMIDE and witnessed subject loss late.
But of course the CASTOR+POLLUX GRAPH does not show four groups within a single experiment. CASTOR and POLLUX are two separate experiments, and assignment of subjects to either CASTOR or POLLUX was not random, so that pre-treatment subject characteristics in CASTOR cannot be assumed to be equal to those in POLLUX, and many other differences undoubtedly exist in the way that the two studies were carried out. Therefore, it would be most unscientific to offer the CASTOR-POLLUX GRAPH as demonstrating the danger of Bortezomib — but that is not the use that the graph is being put to here. Its use here is the legitimate one of inspiring hypotheses that call out to be tested in proper experiments.
Whenever a scientist sees a surprising and large event, he is likely to wonder what caused it, and will begin to guess and to speculate. One may say he begins to hypothesize, and very like comes up with several hypotheses which might account for the event witnessed, and naturally imagines how he might perform tests to see which of these hypotheses can be deemed false and stricken from the list of the viable. That's all we are doing here.
We see a large effect, at least large compared to the other effect that the authors prefer to notice. One hypothesis explaining this effect is that Bortezomib shortens survival while Lenalidomide has no effect on survival. Another is that Bortezomib has no effect on survival, but Lenalidomide extends survival. There are many different combinations, and if the groups shown in the CASTOR+POLLUX GRAPH were run within one experiment (a rat experiment first, and some human version of the rat experiment afterward), it would be possible to reject many of the hypotheses, thus zeroing in on the ones that will eventually emerge as true.
But it might also prove to be the case that the strongest cause has little or nothing to do with either Bortezomib or Lenalidomide, but does have to do with subject characteristics — for example, for one reason or another the POLLUX subjects started out at the beginning stronger in fighting off myeloma, or had a less aggressive variety of myeloma. Such hypothesizing is essential to scientific method. The larger the number of hypotheses that is imagined, the better. Then begins the process of discarding one after another, either on the grounds of evidence already existing, or on the grounds of evidence newly gathered.
What we are left with, then, is that among the viable hypotheses emerging from CASTOR/POLLUX is that when Bortezomib replaces Lenalidomide, that substitution greatly hastens subject discontinuation. As the evidence suggesting this hypothesis is strong and clear, it is reasonable to expect that CASTOR/POLLUX authors and researchers are aware of it, but choose not to investigate it, or even mention it, because doing either would hurt sales of the Johnson & Johnson product Bortezomib. The broader principle being suggested is that Big Pharma chooses to narrow attention to findings which increase revenue, and information that a Big Pharma product may shorten life does not increase Big Pharma revenue, and so that is the eighth disappointment that a scientist notices upon no more than glancing at the CASTOR/POLLUX Overall-Survival graphs.
So far, then, CASTOR/POLLUX disappoint first by its staff receiving Johnson & Johnson payments while failing to disclose their amounts, and disappoint second by failing to cite animal-model precedents for their human clinical trials, and after that disappoint by offering Overall-Survival graphs which exhibit eight defects, the entire package of disappointments and defects outlined so far having been earlier noticed in the Bortezomib-promoting VISTA-San Miguel (2008) (excepting the eighth).
WHAT SCIENTISTS THINK WHEN PROBING BEYOND OVERALL-SURVIVAL GRAPHS
CASTOR/POLLUX continue the VISTA precedent of expanding a two-group experiment (which should have been conducted with 12 subjects per group, for a total of 24, and at one location) to twenty times that number of subjects (I am rounding greatly in this paragraph), and then cutting that bloated behemoth into a hundred slices averaging fewer than five subjects per slice, and entrusting the slices to a hundred investigators scattered all over the globe, scattered even to "rescue countries" to which pharmaceutical manufacturers flock to buy the clinical-trial results that win them product approval from American and Canadian and European regulatory agencies.
The expand-and-slice practice would be inadvisable even if desired outcomes weren't being bought. How, for example, does the central Johnson & Johnson authority guarantee that the 138 CASTOR-Palumbo investigators scattered over 115 sites in 16 countries will learn what they need to know of the 119-page
CASTOR-Palumbo TRIAL PROTOCOL, and isn't it inefficient to have each investigator first go through anything like rigorous training of this voluminous material if he/she is going to run fewer than five subjects?
Ditto for POLLUX-Dimopoulos — its 134 investigators scattered over 135 sites in 18 countries and expected to follow the 111-page
POLLUX-Dimopoulos TRIAL PROTOCOL. Where and when is investigator training going to take place, and to what level of expertise will an investigator be raised when he is scheduled to run only five subjects?
Achieving standardization even within the United States is already difficult enough:
Cancer patient dies after errors during chemo treatment
By: Christina Palladino
Posted: 24Oct2017 07:37PM CDT
Updated: 10:35PM CDT
ST. MICHAEL, Minn. (KMSP) — Officials from the Department of Health are looking into the actions of at least one nurse at the Legacy of St. Michael assisted living facility after a woman passed away from only getting 26 of the 42 scheduled doses of chemotherapy medications in a 12-week period.
A patient diagnosed with multiple myeloma, a blood cancer, was put on a strict schedule of chemotherapy treatments both at home and at a cancer clinic.
The treatments were to start last September and go through April of this year, but according to an extensive report from the Department of Health that medical advice was not followed.
The report details multiple errors including delays in getting the medication into the computer system, which resulted in missed doses and administering the medication improperly.
According to state documents the nurse in question could not provide any training documents or a background check to state investigators.
She told investigators she "shadowed a staff nurse for two days before she was on her own." [...]
And so achieving standardization among investigators working in isolation in remote locations can be expected to be even less successful and even more disturbed by confusion and error.
Also, enrolling subjects all over the world increases their
pre-randomization subject heterogeneity
which makes it harder for randomization to deliver the pre-treatment equality of subject characteristics which is so essential to experimental validity.
San Miguel (2008)
parentheses indicate drug
absent from Control Group
Total = 682
Bortezomib = 344
Control = 338
Total = 498
Daratumumab = 251
Control = 247
Total = 569
Daratumumab = 286
Control = 283
|PAGES OF TRIAL PROTOCOL
A CLOSER LOOK AT THE AUTHORS
CASTOR/POLLUX continue the VISTA precedent of acknowledging a large number of authors scattered all over the globe which, however, is suggestive of pseudo-authorship whereby in exchange for the use of their names, the pseudo-authors get to add another publication to their curriculum vitae, and perhaps receive other consideration — but that amounts to a suspicion aroused rather than an accusation proven.
Distrust of the authors may be intensified upon reading a CASTOR statement which shakes not only our faith that the authors did much authoring, but also shakes our faith that their names at the head of the article can be taken to mean that they vouch for the project's accuracy and completeness and fidelity. Perhaps it is "professional medical writers" who really did the writing, is what the statement below seems to suggest. Perhaps the role of the pseudo authors was to read what the professional writers had written, jot down a few laudatory comments, and sign on the dotted line, as per agreement. But sticking their necks out so far as to personally vouch for accuracy and completeness and fidelity — this is regarded as the obligation of the sponsors and investigators, not of the authors. Is that what is being confessed below?
NEJM CASTOR ARTICLE
Professional medical writers were funded by the sponsor to prepare the manuscript for submission. All the authors reviewed, revised, and approved the manuscript for submission. The sponsor and investigators vouch for the accuracy and completeness of the data from the prespecified interim analysis and for the fidelity of the trial to the protocol.
If the above statement does deliberately try to exempt authors from responsibility, then this may be at odds with prevailing expert opinion, as expressed in the fourth of the four criteria of authorship:
Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
A closer look at authorship data reveals what may be characterized as the sponsor deliberately imposing author compartmentalization. In POLLUX-Dimopoulos, for example, the three numbers in the orange cells above may seem to be telling us everything there is to know about POLLUX authorship, whereas in reality these three numbers conceal the phemomenon of author compartmentalization which can be discovered only by dissecting the raw data, as is accomplished in the orange-headed table below. That is, of the total of 24 authors, 6 work at one address: Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA, in the building shown. This Johnson & Johnson sextet may be conjectured to work collaboratively — they very likely consult and coordinate with each other, can confer with one another by just walking down the hall and sticking a head through a door. Within the POLLUX trial they form a nucleus, perhaps a mission control.
But the remaining 18 authors are not so compacted. They live in 18 different cities scattered over 13 countries. And when a country hosts more than one author, they live in widely-separated cities, as for example the two in Denmark are separated by 237 km, and the two in Canada by 3,414 km (the smallest and largest within-country distances observed). Whereas a first glance at the author list at the top of POLLUX-Dimopoulos may give the impression of 24 scientists working in close collaboration, the analysis below suggests, rather, that collaboration probably does take place within the headquartered nucleus, but the large separation of the remaining three-quarters of the authors presents an obstacle to their doing the same:
24-AUTHOR DISPOSITION in POLLUX-Dimopoulus-06Oct2016
6 POLLUX insider authors employed
at one Janssen R&D facility
Janssen R&D, Spring House PA USA
1. Nushmia Z Khokhar, MD
2. Lisa O’Rourke, MSN
3. Christopher Chiu, PhD
4. Xiang Qin, MS
5. Mary Guckert, MSN
6. Tahamtan Ahmadi, MD
|| 18 POLLUX outsider authors live in separate cities
1. Canada, Calgary, Nizar J. Bahlis, MD 3,414 km
2. Canada, Toronto, Donna Reece, MD
3. Denmark, Copenhagen, Steen Lisby, MD 237 km
4. Denmark, Vejle, Torben Plesner, MD
5. France, Nantes, Philippe Moreau, MD
6. Germany, Heidelberg, Hartmut Goldschmidt, MD
7. Greece, Athens, Meletios A Dimopoulos, MD
8. Israel, Jerusalem, Dina Ben Yehuda, MD
9. Japan, Tokyo, Kenshi Suzuki, MD
10. Korea, Seoul, Sung-Soo Yoon, MD
11. Poland, Poznan, Mieczyslaw Komarnicki, MD
12. Spain, Barcelona, Albert Oriol, MD 485 km
13. Spain, Pamplona, Jesus San-Miguel, MD
14. Sweden, Stockholm, Hareth Nahi, MD
15. UK, London, Neil Rabin, MB, BS, PhD
16. USA, Boston MA, Paul G Richardson, MD 1,363 km 2,974 km
17. USA, Charlotte NC, Saad Z Usmani, MD 1,668 km
18. USA, Houston TX, Robert Z Orlowski, MD
MD = Doctor of Medicine = Medical Doctor
MB = Bachelor of Medicine = British equivalent of MD
BS = Bachelor of Science
MS = Master of Science
MSN = Master of Science in Nursing
PhD = Doctor of Philosophy
Kilometers gives the driving distance to the same-country city one line below. A second distance per line would be to the same-country city two lines below. For example, Boston to Houston is 2,974 km.
The CASTOR data below leads to similar conclusions:
19-AUTHOR DISPOSITION in CASTOR-Palumbo-25Aug2016
6 CASTOR insider authors employed
at three Janssen R&D facilities
Janssen R&D, Spring House PA USA
1. Ming Qi, MD
2. Xiang Qin, MS
3. Tahamtan Ahmadi, MD
Janssen R&D, Raritan NJ USA
4. Jordan Schecter, MD
5. Himal Amin, BS
Janssen R&D, Beerse BELGIUM
6. William Deraedt, PhD
|| 13 CASTOR outsider authors live in separate cities
1. Australia, Melbourne, Andrew Spencer, MD
2. Brazil, Sao Paulo, Vania Hungria, MD
3. Czech Republic, Prague, Ivan Spicka, MD
4. Germany, Mainz, Markus Munder, MD 241 km
5. Germany, Tuebingen, Katja Weisel, MD
6. Hungary, Budapest, Tamas Masszi, MD
7. Italy, Turin, Antonio Palumbo, MD
8. Netherlands, Rotterdam, Pieter Sonneveld, MD
9. Spain, Salamanca, Maria V Mateos, MD
10. Turkey, Ankara, Meral Beksac, MD
11. USA, Atlanta GA, Ajay K Nooka, MD 556 km 1,391 km
12. USA, Jacksonville FL, Asher Chanan-Khan, MD 1,500 km
13. USA, New York NY, Tomer M Mark, MD
It will be noticed that the compartmentalization of outsider authors is not only within-experiment, but holds for the two experiments pooled, as if a city which is home to an outsider author in POLLUX is excluded from being home to any outsider author in CASTOR, and vice versa. Insider Xiang Qin, by the way, is the only author in both POLLUX and CASTOR.
However, as the authors are expected to bear some responsibility for identifying and excluding pseudo-authors, they will find it increasingly difficult to carry out this responsibility the more compartmentalized they are from other authors:
In addition to being accountable for the parts of the work he or she has done, an author should be able to identify which co-authors are responsible for specific other parts of the work. In addition, authors should have confidence in the integrity of the contributions of their co-authors. [...]
It is the collective responsibility of the authors, not the journal to which the work is submitted, to determine that all people named as authors meet all four criteria [...].
And if Johnson & Johnson was in fact enforcing pseudo-author compartmentalization ... why? Compartmentalization seems to bring no benefit to the advancement of science or to the understanding of multiple myeloma or to the health of patients or to the reduction of medical costs. Where is to be found any gain of pseudo-author compartmentalization?
One possible explanation of the enforcement of compartmentalization is suggested by the research of Solomon Asch
indicating that when individuals can plainly see that a group is wrong, they are nevertheless more likely to conform to group opinion when the group is unanimous than when the group contains even a single dissenter. Applied to the present case, an author or investigator who begins to doubt the integrity of the clinical trial would be more inclined to blow the whistle if he/she found even a single other worker pricked by the same qualms. By keeping whistle-blowing-inclined personalities apart, then, a misbehaving research sponsor reduces the probability that they will blow their whistles.
The same moral is delivered by fable — no one dares voice the divergent view that the emperor has no clothes until a child blurts it out.
It may also be noticed that MD is the only academic qualification of 17 of the 18 POLLUX outsider authors, and of all 13 of the 13 CASTOR outsider authors, which is problematic because of the weak training in scientific method that the MD degree requires. MDs who happen to also be competent researchers acquired that skill either before or after their MD training, or alongside it. To assume from the possession of an MD along with outsider authorship of an article that an individual is at the same time a scientist, able to distinguish scientific research from infomercial, is to be wrong most of the time.
PERMIT NO CONFOUNDING
In either CASTOR or POLLUX, the two drugs taken by control-group subjects, and the three drugs taken by experimental-group subjects, produced adverse reactions which were often severe enough to require medication in what is called usually "management", and less often "concomitant medication" or "background therapy", and in the quote below is called "pre-infusion medication" or "post-infusion medication", and which extra medication is constitutes a confounding which might affect the outcomes the researcher is watching, as for example the outcome we are primarily interested in — survival.
The medications used in such management are usually not identified in VISTA/CASTOR/POLLUX, one notable exception occurring with respect to infusion-related adverse reactions, whose description is worded identically in the CASTOR and POLLUX reports, as is acknowledged in the first sentence in the POLLUX box quote below. This description is highly technical, and needs to be glanced at only long enough to be convinced that many different background-therapy drugs are being administered to many subjects, and in so idiosyncratic and ad hoc a manner as to leave no possibility of discerning how they might be affecting survival, and in fact so as to leave no way of ruling out the possibility that the background-therapy drugs are affecting survival more than the clinical-trial drugs are:
NEJM POLLUX SUPPLEMENTARY APPENDIX
and also in
NEJM CASTOR SUPPLEMENTARY APPENDIX
Pre- and Post-infusion Medications
Guidelines for the management of IRRs were identical to that for CASTOR (Palumbo in press). Pre-infusion medication consisted of dexamethasone 20 mg IV (PO if IV was not available) or an equivalent long-acting corticosteroid, paracetamol (acetaminophen) 650 to 1,000 mg IV or PO, and an antihistamine given IV or PO (diphenhydramine 25 to 50 mg, or equivalent). Patients with a higher risk of respiratory complications (e.g., patients with chronic obstructive pulmonary disease [COPD] who have a forced expiratory volume in 1 second of <80%; patients with asthma) were treated with post-infusion medication consisting of an antihistamine (diphenhydramine or equivalent) on the first and second days after all infusions, short-acting β2 adrenergic receptor agonist, such as salbutamol aerosol, and control medications for lung disease (e.g., inhaled corticosteroids ± long-acting β2 adrenergic receptor agonists for patients with asthma; long-acting bronchodilators such as tiotropium or salmeterol ± inhaled corticosteroids for patients with COPD).
Perhaps a source of confounding even more important than background therapy is the VISTA/CASTOR/POLLUX adherance to an "open label" policy, meaning that everybody — physicians and nurses and technicians and lab workers and data-handlers and the subjects themselves — all know who is in what condition, and may feel obligated on a thousand-and-one occasions to nudge the data in the direction that the sponsor needs to get his drug approved. Open label is mentioned under the heading of "Confounding" because it leads to staff acting differently toward the subjects in the two groups, or leads subjects to themselves act differently based on their knowledge of what condition they are in — which differences violate the fundamental requirement of a valid experiment, that only a single difference be allowed between groups, which whether in CASTOR-Palumbo or POLLUX-Dimopoulos is the Daratumumab difference. It is only when a single difference has been allowed that it will be able to take sole credit for any improved health outcome that ensues.
Double-blind, then, in which neither the subject, nor anybody making contact with the subject, knows what treatment group the subject has been assigned to, is not a frivolous embellishment that the researcher is at liberty to discard without penalty, but rather is essential to research integrity and to discard which is sufficient — by itself — to downgrade what might have been a legitimate clinical trial to the status of an infomercial.
HAS THE TIME COME TO STOP DOLING OUT BENEFIT-OF-THE-DOUBT?
In our discussion of VISTA-San Miguel-2008, since we had no evidence that the random assignment of subjects to groups had gone awry, we gave that study the benefit-of-the-doubt by crediting it with having accomplished random assignment properly. However, perhaps the closer look that we have been taking at the quality of Johnson & Johnson publications has given us evidence calling for less liberal indulgence — evidence not just that Johnson & Johnson makes mistakes, but that Johnson & Johnson at every opportunity makes every mistake imaginable, and repeats those mistakes so egregiously and tenaciously that we may be justified in wondering whether a closer look at its random assignment might reveal the same malfeasance there as is revealed in every other department.
Suspicion concerning the integrity of random assignment is heightened when we begin to appreciate the powerful forces arrayed against it, with the following example revealing only the tip of a very large iceberg, and revealing pressure to deviate from protocol random assignment in two ways: one deviation is to admit among the pre-randomization subjects any who are too heterogenous (in this case too sick), and the other deviation is to interfere with random assignment of subjects to groups (in this case by demanding that the particularly-sick subject be assigned to the presumably-efficacious Study-Drug Group).
It seems, in the case of Fred Baron below, that the initial demand of his admission into the Tysabri Study-Drug Group was eventually reduced to the demand of allowing him to receive the same treatment as the Tysabri Group, but without being admitted as a subject within the clinical trial:
WikiLeaks: Dems tried to get donor experimental drug
by Robert King 17 Oct 2016
Former President Bill Clinton, current Secretary of State John Kerry and other top Democrats pressured a pharmaceutical company to give a major donor an experimental drug, according to emails released by WikiLeaks on Saturday. [...]
The emails from October 2008 centered on efforts to get the drug to Dallas Democratic donor Fred Baron, who was suffering from multiple myeloma. In response, Clinton, Kerry and former Democratic senators Tom Harkin and Max Baucus heavily lobbied Biogen, which was the maker of the drug Tysabri.
Tysabri was in clinical trials at the time to treat multiple myeloma, and was previously approved to treat multiple sclerosis.
Bonner said in an email to Podesta that Biogen wouldn't let Baron into the trial because he was too sick, and if the drug failed him then it could skew the outcome of the trials.
Kerry, a senator at the time, called then-Food and Drug Administration Commissioner Andrew Von Eschenbach. He said that Baron needed Biogen to grant a compassionate use waiver to get access to the drug. [...]
Baron eventually got the drug, but he died a week before the presidential election in 2008. [...].
A few details of the above story deserve comment. First, that the politicians interfering with Biogen's research protocol place no value on research integrity. Who cares if the end result of their meddling might be that thousands of patients lose their health or their lives by trusting distorted research? — The only important consideration is to keep political-party coffers full by rewarding donors for their support.
And about Biogen's reason for denying Fred Baron entry into the Tysabri Group — that he was likely to make Tysabri look bad. What is missing here is an expression of a committment to due process not only when such a committment assists in boosting the study drug, but whether it boosts the study drug or not.
And one last peculiarity — the readiness of all concerned to trust that whatever latest drug is being promoted is likely to be the best. One thing that the Fred Baron interveners have probably not been told is that the Tysabri experiment they want Fred Baron to play the role of guinea pig in has never been tried on guinea pigs ... or rats or any other animals. And they have probably also not been told that whatever previous clinical trials claim to have shown Tysabri benefits possibly did so laden with enough violations of scientific method to invalidate their conclusions many times over. And perhaps, finally, those who fought to win Fred Baron access to Tysabri were unaware that concerns had already been raised about its safety, not merely on account of the handful of subjects that Tysabri is thought to have killed, but more importantly that it had never been tested over an interval long enough to reveal how much more capable it was of killing if continued.
Will Tysabri make it back to market?
By Val Brickates Kennedy
Published: May 12, 2005
[...] Tysabri was recalled by Biogen and Elan on Feb. 28 after two members of an MS clinical trial were discovered to have developed progressive multifocal leukoencephalopathy, or PML, an extremely rare but deadly brain infection seen mostly in AIDS patients. One patient died.
A subsequent review of Tysabri patient records revealed a third user also had died of PML, during a clinical trial for the treatment of Crohn's disease. [...]
TYSABRI (natalizumab) — New Safety Information Regarding Progressive Multifocal Leukoencephalopathy (PML)
Health Canada Advisory 2010
PML is a serious disabling neurological condition that can result in death.
The risk of PML increases the longer you are receiving treatment, especially if you have been on treatment for over 24 months. The risk after 3 years of treatment is currently unknown. [...]
Rare cases of a brain infection by JC virus called progressive multifocal leukoencephalopathy (PML) have occurred in patients who have been given TYSABRI. PML can cause disability or death. [...] Signs and symptoms of PML include progressive weakness on one side of the body, clumsiness of limbs, disturbance of vision, changes in thinking, memory and orientation, confusion, and personality changes. [...]
FDA Advisory 2012
There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of TYSABRI will
mitigate the disease. [...]
THE BOTTOM LINE ON DARZALEX=DARATUMUMAB
The bottom line is that just as we earlier concluded that VISTA-San Miguel(2008) was not scientific research but infomercial, we have now no choice but to conclude that neither CASTOR-Palumbo(2016) nor POLLUX-Dimopoulos (2016) show the least improvement in scientific validity, but rather continue to be infomercials so riddled with error as to justify no conclusions whatever, the implications of which bottom line are mind-boggling — that many patients today are being not cured but abused, that patients and insurance companies and governments are being drained of cash to pay for treatments lacking empirical endorsement, that the medical profession is unable to cleanse itself of error at every checkpoint in the process of pharmaceutical evolution, as at the granting of research money, or at the granting of permission to conduct clinical trials, or at the peer review of submitted reports, or at their editorial acceptance for publication, or at the dissemination of research results to the press, or at the stage of regulatory approval for therapy, or at the final step of a practitioner selecting a treatment that fits a patient's malady.▢
Despite reliance on complex and esoteric statistical methods by the producers of the infomercials, they fail to understand the fundamental nature of a science experiment, and how violating that fundamental nature cannot be compensated by later statistical slight-of-hand, no matter how dazzling and mystifying. Applicable to this situation is the recommendation by physicist Ernest Rutherford that "If your experiment needs statistics, you should have conducted a better experiment."
But of course in the case of Johnson & Johnson's VISTA/CASTOR/POLLUX, we are dealing with something quite a bit worse than experiments whose results are so weak as to need bolstering by statistics, we are dealing with infomercials whose conclusions no statistics can validate.
It also follows that if no cause-effect conclusion can be extracted from any particular defective experiment, no "meta-analysis" will be able to extract any cause-effect conclusion from any collection of such defective experiments.