On May 30, 2018 the president signed HR 878, granting terminally ill patients the right to try experimental drugs. While there has been significant controversy surrounding this bill it represents an interesting milestone in the public debate surrounding drug development.
For those unfamiliar with the process, drug development follows a well-established path from discovery to FDA approval.
Once a new compound is identified and has cleared preclinical and animal models, it moves to human Phase I trials.
The intent of these trials is to determine whether the drug is safe. There is no therapeutic intent. If found safe, the drug then moves to Phase II trials that determine whether it is effective. Finally, in phase III the drug is compared with existing treatments to determine relative equivalence or superiority.
However well intended, the process has become slow and costly requiring up to a decade for completion and over a billion dollars for every drug that is FDA approved. A recent study from MIT reported that the success rate for cancer drugs is only 3.4% (Wong, C. H., et al., Biostatistics 2018).
While it is laudable that the FDA seeks to protect the public against ineffective or, worse yet, dangerous drugs patients with life-threatening illnesses do not have the luxury of waiting a decade for a new drug or combination. This is the subject of the Right To Try law.
The impetus for the law came from a family’s desire to provide a treatment to their young son with muscular dystrophy. While his story ended well, with the boy ultimately qualifying for a clinical trial that provided the drug, most cancer patients are not so lucky.
Cancer drug discovery is moving forward at a dizzying pace.
Literally thousands of clinical trials are underway.
While the lure of gene-based (genomic) drug selection seems tantalizing, the reality for studies like the MATCH trial, recently reported at the American Society of Clinical Oncology (ASCO) meeting in Chicago, confirmed that only a tiny fraction of patients actually benefit from these DNA-directed therapies. It will be a very long time before genomic biomarkers (DNA) help select drugs for patients, if ever.
Our group has promoted the use of functional platforms like the ex vivo analysis of programmed cell death that examine cellular biology to identify drugs for patients. Results reveal a 2-fold higher response in patients receiving drugs found active in our laboratory platform and an improved one-year survival.
One of the most frustrating aspects of our work is that which occurs when we identify a novel drug or combination only to find that in the absence of a formal FDA-approval for that specific disease and indication, we cannot obtain the drug. How can we reconcile the patient's desire to obtain a new drug with the need for regulatory oversight and safety?
The recent Right To Try law is designed to address this question.
First, it only applies to drugs that have passed Phase I and have been found safe for patients. As you recall Phase I establishes drug safety. No drug found unsafe goes on for further evaluation. Thus, any patient requesting a drug knows that appropriate oversight has established that it can be administered without undue hazard.
Today, drugs that move from Phase I to Phase II are parceled out to the toniest of institutions. These ivory tower medical centers, generally found in larger cities, hold these sought-after-agents close to the vest, offering them only to those who meet the most stringent criteria for protocol accrual.
If you live in an area removed from a major city, or your performance status, liver or lung functions are just a tick off the inclusionary or exclusionary criteria you are SOL (Simply Out of Luck ;). No matter how much you might want or need the new therapy, it is simply not available to you.
In these instances, the Right To Try law could provide a meaningful advantage to those facing very grim prospects once available standard therapies have failed.
One such patient comes to mind.
A Case of Aggressive Multiple Myeloma
In October of 2016, I consulted with a patient with very aggressive multiple myeloma.
He had received intensive therapy, including a bone marrow transplantation, first in San Diego and later from a tertiary care center near Los Angeles. Brief responses were followed by rapid relapses.
Among the features of his illness was a cytogenetic (DNA chromosome breakage) abnormality associated with poor prognosis known as the t (11, 14) translocation. At the time of our meeting he had not yet received the new monoclonal antibodies recently developed for this disease and I encouraged him to try these agents.
One year later he returned with rapid progression of his disease and I conducted a bone marrow aspirate to submit the myeloma cells for EVA-PCD (Ex Vivo Analysis of Programmed Cell Death) analysis.
The results revealed activity for chemotherapies, but his bone marrow was compromised by disease and prior therapy and I knew that the toxicities could be significant. What struck me most was his myeloma cell’s exquisite sensitivity to a new class of drugs that block the cell survival protein Bcl-2. His cells were the most sensitive we had seen for this class of compounds.
Drugs that target Bcl-2 had already passed Phase I and Phase II and were available for a very select group of chronic lymphocytic leukemia (CLL) patients, but not for multiple myeloma. Clinical trials were underway but the pharmaceutical company was under close scrutiny for any signals, favorable or unfavorable, that might influence an FDA approval.
Attempts with chemotherapy proved briefly effective but toxic. It was obvious that the patient could not tolerate cytotoxic drugs. I then began a diligent effort to obtain this new Bcl-2 drug. I felt confident that he would respond if I could just get the drug.
Today’s pharmaceutical companies are "under the gun" when they allow the use of a drugs before approval.
Good outcomes are of little interest to the oversight bodies, dismissed as anecdotal, but any toxicity, expected or otherwise, can cost the drug company that make a drug available under “compassionate use” a favorable review. Complications, toxicities or unexpected adverse event can derail an otherwise successful campaign to gain FDA approval.
It is no wonder that pharmaceutical companies are hesitant to make drugs available.
For critics of the current law who feel that it has let the pharmaceutical companies off the hook, they may wish to consider the quandary that these companies find themselves in when they act compassionately.
Despite repeated requests, I could not obtain the drug and the patient succumbed to his disease, never having been given the chance to receive the drug that I had carefully chosen for him.
Latest Meeting at ASCO (June 2018)
I have just returned from the American Society of Clinical Oncology (ASCO) meeting in Chicago where I attended many sessions including those on hematologic malignancies.
One presentation was particularly poignant.
They found that patients with multiple myeloma who carry the t (11;14) translocation (precisely the same as this patient) and as predicted in our laboratory model, were uniquely sensitive to Bcl-2 inhibitors, the very drug we had chosen. Indeed, myeloma patients who carried t(11;14) and received the combination of Venetoclax (Bcl-2) plus Carfilzomib, had an a response rate of 100%.!!!!
Here, 18-months later, I sat in the audience at ASCO meeting and all I could think of was this nice gentleman, sitting on the edge of the bed, suffering through drug toxicities, while all he needed was access to a simple oral therapy that almost certainly would have provided the benefit he so desperately needed.
It pains me still to think of him.
The Right to Try Law is not perfect. After all, it leaves much of the responsibility for complications to the physician over the pharmaceutical company. But I, and many of my colleagues, would probably accept that mantle if it meant that we could gain access to a new and more effective therapies.
As one who explores new drugs and combinations every day in my laboratory, I would relish the opportunity to put interesting combinations to the test in service of my patients. Working closely with patients, it is my opinion, that these grateful recipients of our above-and-beyond the call of duty efforts would be unlikely to sue their physician as he or she toiled to improve their outcome.
Most patients appreciate that doctors are on their side.
Under current regulations, pharmaceutical companies gain nothing when they make drugs available on compassionate use; No pat-on-the-back, no attaboys, only the risk of losing FDA approval should an unexpected side effect or complication pop up. Is it surprising that the pharmaceutical companies do not want to make their drugs available?
My Final Thoughts
We need to make our laws work for each individual.
We need to make drugs more available, faster and cheaper. We need to apply every tool at our disposal to make important and lifesaving decisions.
While not perfect, the current Right to Try Law may offer significant benefit, particularly for patients identified in laboratory models who are found likely to benefit from a new PI3-K inhibitor, a BET bromodomain down-regulator, or a drug approved for one indication (disease-type) but not approved for another.
Cancer medicine is a patient-by-patient undertaking.
Our medical institutions, governmental agencies, and reimbursement entities must take into consideration the desperation that advanced stage cancer patients feel and they should work to accommodate these patient’s needs.
The Right to Try laws can open new avenues for patients to pursue personalized care. Though not ideal, I applaud its intent, and look forward to applying it in the many patients for whom we identify unexpected, but potentially effective novel treatments.
As always, I appreciate your thoughts and comments.
Dr. Robert Nagourney, has been internationally recognized as a pioneer in cancer research and personalized cancer treatment for over 20 years. He is a TEDX SPEAKER, author of the book OUTLIVING CANCER, a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology helping cancer patients from around the world at his Nagourney Cancer Institute in Long Beach, California. For more info go to NAGOURNEYCANCERINSTITUTE.COM