Maybe you can answer why Oncologists are able to sell their own drugs.. isn't that a conflict of interest? Or maybe how about writing a paper on the OPPOSITE of drugs and why NOT everyone gets cancer and WHY don't some get cancer and others do? Might be fascinating huh?
Clinical inertia grows rapidly amongst the physicians and scientists of a country that is becoming evermore distracted by the noise of partisanship, Big Pharma cronyism, and plain ol' comfort. "Thou shalt be nice" is the 11th commandment, and it isn't nice to ruffle feathers. It isn't nice to do something other than "the way we've always done it". It isn't nice to change RCT design of oncology drugs bc the manifold promises of hope by academic elites and pharmaceutical CEOs are based on the success of RCTs with unethical control arms. Promises of hope for their bank accounts, mind you...
Designing cancer trials is, and was, challenging. Standard of care as a comparator to standard of care plus the new treatmemt is usually the goal, but choosing a standard of care for a multinational study can be difficult. The standard of care can vary greatly by geography, based on what products are approved and available and clinical practice. That variability impacts the liklihood of detecting a treatment effect of the tested drug. The rarity of many cancers requires a multinational trial in order to complete the study in reasonable amount of time. Blockbusters are few and far between, so most of the products we're testing may only have benefit for 20 to 30% of patients. But this 20 to 30% may have different baseline disease characteristics from the 20 to 30% that respond to another available therapy, so both migjt be needed.
None of this is said to defend the design and conduct of the cassiopia trial, but to highlight the challenges that we face in testing new oncology products. If in that trial, the informed consent form was not updated to reflect the updated standard of care options, then fault lies with regulators, the company, the independent ethics committee, and any data safety monitoring committee ever seeing the study.
It's worth bearing in mind that the example described by Manni is not a one off. Judging from Vinay's work (his book Malignant, his writings and plenary session), what Manni describes is actually common to many many RCTs of anti-cancer drugs conducted by US pharma companies in the 3rd world. at least in the case Manni described, although the control arm should have been switched to standard care, the trial was actually done in 1st world countries.
Interesting article. This gets into the thorny bit of how an RCT should be conducted (typically over years in phase 3 guise that looks at clinical endpoints) when the comparator arm (be it placebo or active comparator) should have changed in light of subsequent evidence that emerges during the study, be it in enrollment or follow-up phase.
In this case, there may have been equipoise about use of that other agent as active comparator/standard of care, at least at beginning of trial. It is curious that there was no protocol amendment after it became standard of care outside of the study. It does bring into question how foundational ICH-GCP principles of subject safety were applied in this case.
Of course, changing the protocol significantly (such as adding an active comparator instead of placebo) greatly affects study interpretation. But as Dr. Prasad notes in the Foreward, not doing so will greatly impact the downstream clinical significance of its results.
Of course, none of this will help the growing cynicism towards big pharma (or the FDA). Achieving the right balance btw corporate gain vs innovation remains elusive.
I was taught that a trial is only ethical if it is *unknown* which arm would have the better outcome. Was there no data safety monitoring board on the CASSIOPEIA trial? Or does outside data, showing the trial is no longer ethical because which arm has better outcomes is now known, not fall under their bailiwick? Does true informed consent, a notion that seems to be almost a distant memory, as it was intended, not extend to updated information during a trial, when there is new information pertinent to a subject's informed decision to remain in the study or not? We do have to guard against situations like those that happened with AZT and the COVID injections, though, where the trials were stopped, blind broken, and placebo/comparator arm given active intervention after only a very short period, since there's no way to know about longer-term adverse events than to have a placebo/comparator arm.
If trial controls are being fudged there is only one reason. Under normal state-of-the-art RCT's most of these new drugs would fail miserably. Therefore, they must be hacked by big pharma to have any chance of being approved by the FDA, which itself is under severe scrutiny for its conduct during the last 3 years. And in many instances, the new drugs are no better than the old but sell for ungodly prices. What a racket while the patients are the guinea pigs and the bag-holders.
Thank you Dr. Mohyuddin for your insight on this challenging, complex and important subject. Having spent the last year fighting myeloma we have learned that the patient and family needs to do significant reading, thinking and consulting on decisions around clinical trials. While they are important in advancing our knowledge, to do so at the expense of the patient seems unethical. You are a true patient advocate.
Maybe you can answer why Oncologists are able to sell their own drugs.. isn't that a conflict of interest? Or maybe how about writing a paper on the OPPOSITE of drugs and why NOT everyone gets cancer and WHY don't some get cancer and others do? Might be fascinating huh?
Clinical inertia grows rapidly amongst the physicians and scientists of a country that is becoming evermore distracted by the noise of partisanship, Big Pharma cronyism, and plain ol' comfort. "Thou shalt be nice" is the 11th commandment, and it isn't nice to ruffle feathers. It isn't nice to do something other than "the way we've always done it". It isn't nice to change RCT design of oncology drugs bc the manifold promises of hope by academic elites and pharmaceutical CEOs are based on the success of RCTs with unethical control arms. Promises of hope for their bank accounts, mind you...
Thank you for this very thoughtful blog. Next steps?
1. File FOIAs with the regulators and ethics committees involved, and turn this into a paper
2. Find a greedy lawyer to file a class action lawsuit
Just thinking aloud...
Designing cancer trials is, and was, challenging. Standard of care as a comparator to standard of care plus the new treatmemt is usually the goal, but choosing a standard of care for a multinational study can be difficult. The standard of care can vary greatly by geography, based on what products are approved and available and clinical practice. That variability impacts the liklihood of detecting a treatment effect of the tested drug. The rarity of many cancers requires a multinational trial in order to complete the study in reasonable amount of time. Blockbusters are few and far between, so most of the products we're testing may only have benefit for 20 to 30% of patients. But this 20 to 30% may have different baseline disease characteristics from the 20 to 30% that respond to another available therapy, so both migjt be needed.
None of this is said to defend the design and conduct of the cassiopia trial, but to highlight the challenges that we face in testing new oncology products. If in that trial, the informed consent form was not updated to reflect the updated standard of care options, then fault lies with regulators, the company, the independent ethics committee, and any data safety monitoring committee ever seeing the study.
It's worth bearing in mind that the example described by Manni is not a one off. Judging from Vinay's work (his book Malignant, his writings and plenary session), what Manni describes is actually common to many many RCTs of anti-cancer drugs conducted by US pharma companies in the 3rd world. at least in the case Manni described, although the control arm should have been switched to standard care, the trial was actually done in 1st world countries.
Interesting article. This gets into the thorny bit of how an RCT should be conducted (typically over years in phase 3 guise that looks at clinical endpoints) when the comparator arm (be it placebo or active comparator) should have changed in light of subsequent evidence that emerges during the study, be it in enrollment or follow-up phase.
In this case, there may have been equipoise about use of that other agent as active comparator/standard of care, at least at beginning of trial. It is curious that there was no protocol amendment after it became standard of care outside of the study. It does bring into question how foundational ICH-GCP principles of subject safety were applied in this case.
Of course, changing the protocol significantly (such as adding an active comparator instead of placebo) greatly affects study interpretation. But as Dr. Prasad notes in the Foreward, not doing so will greatly impact the downstream clinical significance of its results.
Of course, none of this will help the growing cynicism towards big pharma (or the FDA). Achieving the right balance btw corporate gain vs innovation remains elusive.
I was taught that a trial is only ethical if it is *unknown* which arm would have the better outcome. Was there no data safety monitoring board on the CASSIOPEIA trial? Or does outside data, showing the trial is no longer ethical because which arm has better outcomes is now known, not fall under their bailiwick? Does true informed consent, a notion that seems to be almost a distant memory, as it was intended, not extend to updated information during a trial, when there is new information pertinent to a subject's informed decision to remain in the study or not? We do have to guard against situations like those that happened with AZT and the COVID injections, though, where the trials were stopped, blind broken, and placebo/comparator arm given active intervention after only a very short period, since there's no way to know about longer-term adverse events than to have a placebo/comparator arm.
If trial controls are being fudged there is only one reason. Under normal state-of-the-art RCT's most of these new drugs would fail miserably. Therefore, they must be hacked by big pharma to have any chance of being approved by the FDA, which itself is under severe scrutiny for its conduct during the last 3 years. And in many instances, the new drugs are no better than the old but sell for ungodly prices. What a racket while the patients are the guinea pigs and the bag-holders.
Thank you Dr. Mohyuddin for your insight on this challenging, complex and important subject. Having spent the last year fighting myeloma we have learned that the patient and family needs to do significant reading, thinking and consulting on decisions around clinical trials. While they are important in advancing our knowledge, to do so at the expense of the patient seems unethical. You are a true patient advocate.