Wafik El-Deiry analyzes Freireich’s “Seven Laws To Protect Against Obstacles To Clinical Research”

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In 1974, The Cancer Letter published a story listing seven proposed “laws” postulated by of one of oncology’s wise men, Emil J Freireich (The Cancer Letter, May 14, 1976). 

Freireich, who played a key role in curing childhood leukemia, had views that seemed to be intended to engender debate, and the David A. Karnofsky Memorial Lectureship at the American Society of Clinical Oncology 1976 annual meeting gave him a podium to say what he really thought about the future path of cancer research. 

Consider Law No. 3:

“If we must experiment with patients to obtain medical information, then we had best do without that information. It cannot be necessary to have a bad result before we can be convinced of the good results.” 

Freireich elaborated on these views during a series of debates with Charles Moertel, professor of oncology at Mayo Clinic who advocated for high-quality research and scientific rigor (The Cancer Letter, April 20, 1979; Feb. 20, 1981; April 17, 1981).

Emil “Tom” Frei III, former director and physician and chief of Dana-Farber Cancer Institute, described the third debate as “the great Charlie Moertel shootout,” while Moertel called it the “the second half of the Jay and Charlie show.”

How have the Freireich laws held up today, 46 years after the 1976 Karnofsky Lecture?

The Cancer Letter asked Wafik El-Deiry, director of the cancer center at Brown University, to review  the Freireich laws  in the context of today’s science, clinical trials methodology, and ethical standards.

  1. The Clinical Investigator’s Creed: The primary beneficiary of clinical research is the patient participating in that research.

Sure, it is good to have that as an MO. Investigators do benefit professionally and scientific knowledge advances too, so there are other beneficiaries. Both of those are major outcomes. In phase I trials, patient volunteers may not benefit at all. 

But every blockbuster drug in oncology had to start in a phase I trial so of course patients can benefit from miracle drugs such as Gleevec (against BCR-ABL), Herceptin (against Her2/Neu), larotrectinib (against NTRK fusions), selpercatinib (against Ret fusions), sotorasib (against KRAS G12C), etc. 

So, in general it is correct to say “A major beneficiary of clinical research could be the patient participating in that research.” If one takes into account that a patient may consider it a personal benefit that others may ultimately benefit from their clinical trial participation then the statement could be stronger: “A major beneficiary of clinical research is the patient participating in that research.”

  1. Always be prepared for success, because failure creates few problems… If the clinical investigator is not optimistic in his choice of new treatments for his patients, who in the health care system will be? We have to offer this optimism to our patients so that they also feel that the drugs to which they are being exposed and the treatments which they are receiving do have prospects for dramatic changes in outcome for the better. There have been dramatic breakthroughs in the clinical investigations of cancer and virtually all of these have been initiated by optimistic individuals in sequential series of patients, making quantitative observations. A strategy which has been effective in the past and will be effective in the future.

In 2021, clinical investigators are optimistic and hopefully also realistic. But this is also a time where some who are realistic may not be aware of certain new technologies and therapeutics that are life-saving even for patients with poor performance status or who are in hospice. So, while trying to contain healthcare costs and show compassion and follow patients’ wishes, it is important to maintain some balance or equipoise from what scientific advances are bringing to improve patient outcomes.

It should also be stated that clinical research is not about optimism. While physicians caring for their patients bring hope and clinical trials bring hope, committed clinical researchers try to help their patients by offering reasonable options based on scientific advances that have led to open clinical trials that their patients may be eligible to enroll in. It is really the obligation of every good physician to consider the options that could help their patients and to not withhold information that either widens disparities or deprives patients from opportunities to participate in clinical trials through informed consent procedures.

It is really not the optimism of individuals that leads to new clinical trials and breakthroughs as much as commitment of individuals to advocate for patients in advancing the science in which they believe, and which is based on data that supports the trials. The FDA does not approve drugs based on optimism and companies do not develop drugs based on the views of optimistic individuals. Within academia, optimism is not what leads to career success or faculty promotions.

But optimism is better than pessimism in general as an outlook, as long as it is not misleading. The glass is really half full.

  1. If we must experiment with patients to obtain medical information, then we had best do without that information. It cannot be necessary to have a bad result before we can be convinced of the good results.

Human experimentation is necessary to develop new approaches to prevent and treat cancer. The ethics of human experimentation are such that in the earliest trials (phase I) few are treated with no expectation for benefit in order to advance knowledge and help others. Of course, no drug or drug combination gets to clinical trials without promising preclinical data or an otherwise compelling rationale to repurpose or expand a drug label. 

For new drugs, no drug company wants the drug they prioritized for clinical testing to fail as that impacts on their business and investors. The FDA monitors clinical trials closely and must give permission for such trials to proceed with an IND approval in the United States. 

In general, while patients in phase 1 trials expect no benefit, some phase 1 trials of targeted anti-cancer precision therapeutics have had fairly high response rates and there are examples of drug approvals after only a single arm early phase trial (ceritinib for ALK+ NSCLC or larotrectinib for NTRK fusion-driven cancers). 

A tricky situation with first-in-human trials is that (in the interest of safety) the starting dose is not infrequently way below a dose that would be expected to have any efficacy. A reasonable solution would be intra-patient dose escalation with informed consent, and as is already done, a minimum number of patients are treated with such doses, i.e., one patient. 

Well-designed and well-conceived clinical trials need not have bad results, and if rationally designed, and biomarker driven, then things are moving where adverse consequences are minimized from clinical trial participation. 

So, “we must provide the clinical trials option, if available, to patients in order to improve their own care, as well as the care of others in the future.” Clinical investigators already strive to have trials in their portfolio to cover the landscape of needs within their practice or disease area.

  1. The best therapeutic research gives the best results.

In general, that is an accurate statement although one has to be clear on what “the best therapeutic research” actually means. 

Serendipity plays a role and there is some randomness (how penicillin was discovered). A recent example this author was involved with (and I do have a COI) is that an early phase trial in GBM at MGH that enrolled 17 patients had two exceptional responders who turned out to have H3K27M-mutated gliomas that are now known to have a 20% response rate to ONC201/TIC10 and an over 40% disease control rate in that population of patients with aggressive midline gliomas. It could be added that in this case, the “best therapeutic research” started at the bench asking fundamental questions about cancer cell death, drug resistance, tumor suppressor gene pathways and innate immune tumor surveillance. 

This basic research led us in 2007 to carry out a functional cell-based phenotypic drug screen in the El-Deiry lab at U. Penn that identified TIC10 (TRAIL-inducing compound #10) as a small molecule with anti-tumor effects including colon, breast, lung cancer, lymphoma, and brain cancer in an orthotopic model. 

While chemical modifications were made subsequently (e.g. ONC206 that has entered a clinical trial at the NCI and ONC212 that is expected to start clinical testing in 2023), the originally identified TIC10 is the compound that ended up having clinical efficacy in patients with brain tumors originally given as a pill on an every 3-week schedule and is currently used in weekly dosing in the ongoing trials of ONC201/TIC10. 

Other very good examples from years ago include Gleevec whose design was based on structure of BCR-ABL, or the Bcl2 inhibitors whose original design in work by Steve Fesik involved “SAR-by-NMR” to create high affinity inhibitors by chemically linking two low affinity inhibitors that bind to these anti-apoptotic proteins. 

The rational scientific design of therapeutics based on understanding of cancer biology and drug resistance mechanisms is clearly an approach that can lead to good results. New ideas come from genomics and computational biology in 2021 and this is available to all those interested in developing drugs. 

Learning about resistance mechanisms is essential to stay ahead and have options for patients when current therapies are no longer working. In the era of immunotherapy, ways of combining any and all other therapy options to boost immune responses and leverage the advances in immunotherapy could be very helpful. 

Figuring out who is likely to be helped and who will not be helped has become a high priority in 2021. Each patient with advanced cancer has only so much time to try new treatment options. Helping patients by prioritizing the options (whether standard of care or clinical trials and which ones) and figuring out based on available information their chances of benefit could give great results. 

Incorporating all knowledge including genomic tumor boards and genomics expertise of colleagues is essential although there is the element of speed, again as this could make a difference over a few months in the “number of tickets” a patient has to try new treatments. The faster they are instituted and discontinued if they are not working the better off the patient is as far as having more options. 

Finding an option that stabilizes or shrinks the tumor when disease is advanced and metastatic translates into benefit for patients usually with prolongation of life for that particular individual. Goals should always be discussed with patients including quality of life and what patients hope to achieve if they are to have a limited amount of time, given realistic expectations that are shared as part of the discussion.

  1. Instead of the admonition that the physician should as a first principle “do no harm,”  [which is] a particularly offensive admonition since that requires no action at all. Do what can possibly be done, more important, do that which is necessary. We cannot turn our backs on any part of the cancer problem. We must investigate problems in the clinic as they present themselves. We are required to care for the elderly and the young, for acute leukemia and for lung cancer…. The clinical scientist must be in the vanguard of physicians, emphasizing the prospects for a continuously improving outlook and for the achievements of clinical research.

These are lofty ideals and all physicians strive to help their patients in every aspect of their care. Doing no harm is not mutually exclusive with doing everything possible or not turning our back especially when the care plan is arrived at between physician and patient. 

The modern-day problem is that not infrequently the “system” doesn’t help. It invariably gets back to money. So, doing “what can possibly be done” may be expensive and so today’s generation is very sensitive to that. 

In the past it isn’t that physicians or others weren’t concerned about costs. They were entrusted with the decisions to help patients in the way they deemed appropriate after what amounts to decades of educational training and clinical experience. We have gone too far, in this authors view, in terms of financial constraints, over-regulation, and evidence-based medicine where a physician can basically no longer in various settings have a prescription executed for their patient or pursue a treatment that is less mainstream or by guidelines. 

It is shameful this is more the norm now in today’s healthcare system, and has led to the destruction of medicine in some ways in the US. However, it is also clear that Artificial Intelligence (AI) will not any time soon replace the role of the physician in the Oslerian tradition. 

With all the regulation and oversight and evidence-based medicine, healthcare costs in the U.S. are higher than other countries, and life expectancy is lower. Someone with appropriate authority and insight has to look at that in deciding how to improve things.

Another comment that needs to be made is that there are two factors that have hurt innovation, progress, and clinical advances through research in the U.S.: 

1- HIPAA rules that are misinterpreted and that essentially have made it very difficult to do research due to overregulation. Of course, human subjects research should have proper oversight and be done according to ethical practices with all permissions and informed consent in place. I have almost never met anyone who would stand in the way of sharing their own health information if their identity is kept confidential. But today’s HIPAA rules make it difficult for anyone trying to do clinical research, as if clinical investigators are “the bad guys” who need to be constantly policed. This is a general symptom of healthcare systems that have plenty of administrators and lawyers, and it is only getting worse every day. Those who bring up issues to try and improve things shouldn’t be vilified or penalized in any way. 

2- The electronic record and the inability to share data. In the era of genomic medicine, in today’s health care system, we are still scanning faxed documents into clinical records, and clinicians, as I do regularly, enter the gene names and mutations from genomic tests or liquid biopsies into the electronic record. In some health systems the electronic records are siloed in some cases because certain constituencies did not pay exorbitant fees to use a system that in some ways has been in beta-testing for decades. 

Doing no harm is not mutually exclusive with doing everything possible or not turning our back especially when the care plan is arrived at between physician and patient.

Access to clinical imaging results is cumbersome, and it is easier to access the forms for ordering a blood or other send-out test than the test result. This in part occurred years ago because the end-users who care for patients didn’t have a proper seat at the table as these electronic record systems were designed primarily to facilitate billing (and not clinical care or research). And digital pathology that should have been implemented a decade ago is still way off in the future. 

None of these obstacles and challenges help physicians do what’s best for their patients while doing no harm, and these challenges are extremely burdensome for physicians, waste their time and do nothing to address healthcare disparities, inequities or access to care, clinical trials or new drugs. It’s a shame if the electronic records will take a couple of generations before they can be useful for clinical research. 

The issues of HIPAA privacy rules, greed by for-profit entities and non-profit healthcare systems must be brought under control in order to address these complicated problems. The physician-patient relationship, the art of medicine, and the place of physicians in healthcare must be restored. Physicians and their professional societies must take a more active role in the interest of their patients at these societal and regulatory levels.

  1. The best patient care, or patient service, is clinical research. If there is documented progress from the discovery of new treatment, then it should follow that the patients participating in such research are themselves the beneficiary of those new advances, in contrast to those patients not participating in clinical research.

The best patient care or patient service is not necessarily clinical research, although consideration of clinical trials should be part of all clinical care. This is hampered by the tight inclusion criteria within clinical trials that exclude all but the healthiest of patients. This often skews results because the healthiest patients who qualify are those likely to have the best outcomes and better tolerate treatment side effects. 

Clinical research could be vastly improved if trials are more inclusive of the full age spectrum and allow for co-morbidities that are relevant to those who will be taking the treatments after their approval. 

The field now appreciates that and many are working to address this. It has become clear that patients who seek care at major academic centers such as academic cancer centers have better outcomes because of the opportunity to participate in clinical trials that may not be available in the community. 

In a healthy ecosystem, collaboration between community physicians and their academic colleagues yields the best results for patients in terms of balancing convenience and access to the latest advances including new drugs. It should be remembered that every blockbuster drug that has received FDA approval went through clinical trial testing and was made available to patients who participated in those trials (and those drugs weren’t really available to anyone else for clinical use). There are numerous examples of long-term survivors who received their life-saving drugs as a direct result of seeking out and participating in a clinical trial.

  1. No. 7 is a refutation of “the Regulator’s Creed—the general solution to a specific problem will soon become a specific problem requiring a general solution.” Drug review and informed consent procedures are designed to protect against the occasional abuse. It is a great human weakness to generalize from exceptions. As scientists, we know that the best solution to a specific problem is a specific solution. We should attempt to prescribe regulatory procedures which accomplish our objectives without interfering with research.

The statement is cryptic and unclear that a general solution becomes a specific problem requiring a new general solution. 

Hints, major discoveries, and breakthroughs can have their origins in anecdotes. Are all of these borne out? Of course not. Regulatory procedures by well-meaning individuals do hamper research and need checks and balances that are currently lacking. It is unconscionable to delay clinical trials in some instances by 6 months, or 1-2 or more years due to various obstacles. 

Too many ideas remain untested due to resource constraints and a regulatory system that is so distant from the interests of the very patients they are trying so hard to protect. If “occasional abuse” is in fact rare, say one in 100,000 or a million, then we have created a system that is defeating its purpose by not recognizing or addressing the real harm of delaying clinical research. We are speaking about abuse as in rogue, unethical individuals, not in any way diminishing the importance of review of the many details that optimize safety and excellent clinical trial design in every way, and those safeguards that protect vulnerable individuals.

Wafik S. El-Deiry, MD, PhD, FACP
American Cancer Society Research Professor; Director, Cancer Center at Brown University; Director, Joint Program in Cancer Biology, Brown University and Lifespan Cancer Institute; Attending physician, hematology/oncology, LCI, Mencoff Family University Professor, Brown University; Associate dean, Oncologic Sciences, Warren Alpert Medical School, Brown University
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Wafik S. El-Deiry, MD, PhD, FACP
American Cancer Society Research Professor; Director, Cancer Center at Brown University; Director, Joint Program in Cancer Biology, Brown University and Lifespan Cancer Institute; Attending physician, hematology/oncology, LCI, Mencoff Family University Professor, Brown University; Associate dean, Oncologic Sciences, Warren Alpert Medical School, Brown University

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