First of all, since my last CAR-T related post here was made back in April 2017, Saul recently contacted me to inquire if I was still following CAR-T companies and had any thoughts now that Kite has been acquired. I’m still in macro-mode, going through tons of info and research that I found overwhelming and lacked sufficient/available time to reduce it for relevancy in concise, cogent posts to make here. Anyway, I’m now focused on the cancer clinical trial process for CAR-T therapies as well as other cancer treatments. Here’s why.
When innovation in oncology is at an all-time high, there is now a serious short supply of clinical trial participants, particularly in cancer, leaving academic and institutional researchers, bio-tech companies and pharmaceutical companies desperate for patients to participate in their research. Consider the following:
• Approximately only 3% of adult cancer patients participate in clinical trials, according to data presented by Margaret Mooney, Chief, Clinical Investigations Branch, Cancer Therapy Evaluation Program within NCI (National Cancer Institute), and Musa Mayer, breast cancer advocate of AdvancedBC.org.
• 40% of trials failed to achieve minimum patient enrollment, and more than three of five phase III trials failed to do so, according to an analysis by Steven Cheng of more than 500 NCI Cancer Therapy Evaluation Program (CTEP) trials.
• The failure of clinical trials to enroll enough patients moves health care further away from evidence-based practice and represents a tremendous amount of wasted effort.
• Clinical trials are the scientific soul of cancer-cure advances, but nearly 20 percent of these publicly funded studies fail to draw enough patients to render verdicts on experimental therapies. That failure rate represents stalled progress in the pursuit of better cancer drugs and techniques – and “a waste of scarce human and economic resources,” according to a study by Fred Hutchinson Cancer Research Center and the University of Washington on 12/29/15. Fred Hutchinson is partnered with Juno Therapeutics and Memorial Sloan Kettering in CAR-T research.
https://www.fredhutch.org/en/news/center-news/2015/12/one-in…
It might be helpful here to reiterate the typical clinical trial process.
The clinical trials process for gaining regulatory approval of a new drug has traditionally been described in five discrete phases. Each phase seeks to answer a different set of questions. An increasing number of volunteers are included in each phase as the trial progresses and attempts to build a case that an experimental drug or treatment is safe and effective against the disease or condition it is intended to treat.
Phase 0 trials are exploratory, first-in-human studies designed to determine whether a drug affects the human body as expected from earlier preclinical, animal studies. These trials involve a small number of people (10–15) who receive a low, nontherapeutic dose of the investigational drug. These preliminary trials help companies rank a number of different drug candidates in their pipeline and make decisions about which candidates should be developed.
Phase I clinical trials test an experimental drug or treatment for the first time in a small group of people (20–80) over the course of a few weeks or a month. Their goals are to assess the safety of the drug or treatment, find a safe dosage range, and identify any side effects.
In Phase II trials, a larger group of people (100–300) receives the experimental drug to determine whether it is effective and further evaluate its safety. These trials involve subjects with the target disease and usually last months.
Once preliminary evidence from phase II reveals that a treatment is effective, Phase III trials are designed to fully examine the risk/benefit profile of an experimental drug or treatment and test it over a longer period of time in a broader population (1,000–3,000). Because these trials are the last phase in the pre-approval process, they are often referred to as “pivotal” trials.
Phase IV, or post-marketing, trials take place after a drug has been approved. They provide additional evidence on the risks and benefits of the drug or treatment and how it can be used optimally.
So given a shortage of participants and time is critical, cancer researchers turn to the FDA, which acknowledges that speeding the availability of drugs that treat serious diseases are in everyone’s interest, especially when the drugs are the first available treatment or if the drug has advantages over existing treatments. The FDA offers four distinct approaches to making such drugs available as rapidly as possible:
• Priority Review: A process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.
• Breakthrough Therapy: A process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.
• Accelerated Approval: These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint.
• Fast Track: a designation that means FDA’s goal is to take action on an application within 6 months.
The University of Pennsylvania /Novartis’s CTL019 for acute lymphoblastic leukemia (ALL) received breakthrough status and became the first CAR-T therapy to receive final FDA approval.
Some cancer researchers seek orphan status from the FDA supposedly for a drug or biological product to treat a rare disease or condition upon request of a sponsor. The term "rare disease or condition’’ means any disease or condition which
(a) affects less than 200,000 persons in the United States, or
(b) affects more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will recovered from sales in the United States of such drug.
According to Medscape, bio-tech and drug companies are “gaming” the orphan drug system due to loopholes in the Orphan Drug Act (ODA).
http://www.medscape.com/viewarticle/856580
For examples, the FDA granted orphan status to Juno’s JCAR015 and Kite’s KTE-C19 for refractory aggressive non-Hodgkin’s lymphoma.
https://pharmaphorum.com/news/kites-car-t-therapy-most-valua…
Now, back to the main issue. Why is patient participation so low for cancer clinical trials? Some of the barriers to participating in clinical trials cited most frequently by patients in an analysis of 23 oncology studies and 6,000 patients were:
• fear of a reduced quality of life,
• concern about receiving a placebo,
• potential side effects,
• concern that the experimental drug might not be the best option
• inconvenience of participation,
• dislike of randomization,
• wanting one’s own doctor to make decisions,
• feeling coerced, and
• loss of control over treatment decisions.
The single most influential factor in enrolling patients in clinical trials is physician influence. At present, the biggest barrier in recruitment is lack of encouragement or support from the attending physician.
Here are other factors that I have found that impact participation in clinical trials:
• The type of cancer affects the number of available and willing participants. For example, the population afflicted by bladder cancer (in the U.S. the 4th most common cancer in males and the 12th most common cancer in females) is older and frailer than those afflicted by other cancers. These patients are left with no other options aside from participating in a clinical trial to delay or avoid surgery.
• Financial concerns about participation in clinical trials among patients with cancer (you can read about the details in this Journal of Clinical Oncology article:
http://ascopubs.org/doi/full/10.1200/jco.2015.63.2463 )
• Health/Medical insurance coverage. It’s important for participants to know which costs they will have to pay before they join a clinical trial. Here are some excellent websites that address this concern:
Health Insurance Coverage of Clinical Trials
http://www.cancer.net/navigating-cancer-care/how-cancer-trea…
NIH/National Cancer Institute
Paying for Clinical Trials
https://www.cancer.gov/about-cancer/treatment/clinical-trial…
Insurance Coverage and Clinical Trials
https://www.cancer.gov/about-cancer/treatment/clinical-trial…
American Society of Clinical Oncology (ASCO) Insurance Coverage of Clinical Trials (includes state laws and cooperative agreements)
https://www.asco.org/research-progress/clinical-trials/insur…
UnitedHealthcare Clinical Trials: Coverage Determination Guideline
https://www.unitedhealthcareonline.com/ccmcontent/ProviderII…
Travel and transportation expenses are excluded from coverage. These include, but are not limited to, the following examples:
o Fees for all types of transportation (examples include, but are not limited to: personal vehicle, taxi, medical van, ambulance, commercial airline, and train)
o Rental car expenses
o Mileage reimbursement for driving a personal vehicle
o Lodging
o Meals
In a recent documentary, Dr. Carl June, the leader of the University of Pennsylvania/Novartis collaboration, commented: ?“At this point in the U.S. only about 10% of adults go on clinical trials for cancer because it cost them to be on the trial. Sometimes, people come across the county, and they have to stay here really about a month on our trial. Now some of them have come in their RVs and slept in our parking lots. [He makes an emotional pause here] But the system doesn’t have to be that way.”
Bottom-line:
Investors in companies that need to run their therapies and drugs through the gauntlet of clinical trials for FDA approvals might find it prudent to be aware of the type of clinical trial approach and the progress and status of each phase. Companies normally provide this info at their websites in news releases, quarterly reports and corporate presentations. The NIH provides an excellent free service at its ClinicalTrials.gov website. If investors do not understand clinical trial findings in corporate progress and status reports, they could contact investor relations for more info.
From a macro-view point, the entire clinical trial system and process needs a major overhaul. This has been known and said too often in the past.
Back in June 2011, George Sledge, the outgoing President of the American Society of Clinical Oncology and one of the country’s top breast cancer researchers, told his colleagues to prepare for a new era in which rapidly advancing genetic technology will change the way cancer is treated for the better – but also force doctors to change the way they invent and test drugs and care for patients. Sledge said, “Cancer doctors are entering an era of “genomic chaos,” a phrase that describes both the genetic madness that makes healthy cells turn into deadly cancers and the instability that incorporating rapidly advancing genetic technology into cancer care will bring. The way clinical trials are run will need to change dramatically. New kinds of electronic health records will need to be created to collect data, inform doctors instantly of new results, and track how good a job physicians are doing.” Sledge argued that doctors need to face up to this blast of new technology.
According to a recent 6/15/2017 Forbes article “Cancer’s Big Infrastructure Problem,”
https://www.forbes.com/sites/matthewherper/2017/06/15/cancer…
“That infrastructure [in Sledge’s above statement] still does not exist, despite all the talk of cancer moonshots. Clinical trials need to be less expensive, and more patients need to be enrolled in them. Why would patients with no other hopes not get access to DNA sequencing and targeted medicines? They need the drugs, and we need their data! Right now, new better cancer drugs are being developed primarily because their prices are so high that it makes economic sense for companies to go out and find patients to test them in. This is not a problem we should be solving with an individual company’s willingness to cut through the forest. We should be creating roads for everyone to use.”
For my next post, I will try to go back to update and complete a draft post that I started last May, but never got around to completing it that will add to my initial post about personalized CAR-T therapy (e.g., University of Pennsylvania/Novartis) versus universal CAR-T therapy (Cellectis/Servier/Pfizer).
Here’s some background on why I am interested in cancer research and remedies. As a Vietnam War U.S. Navy veteran who was exposed to Agent Orange and suffered one of the 14 presumptive diseases that qualified me for compensation for a service connected disability, my highest priority is getting as many Vietnam War U.S. military veterans suffering any of these diseases and PTSD into the VA compensation system and healthcare system. 6 of the 14 presumptive diseases are cancers, i.e., chronic B-cell leukemias; multiple myeloma; non-Hodgkin’s lymphoma; prostate cancer; respiratory cancers of the lung, larynx, trachea, and bronchus; and soft tissue sarcoma. This year, bladder cancer and a host of other maladies are up for VA final approval to be added to this list.
Getting these aging deserving veterans in is a daunting enigmatic frustrating task for their immediate families and close friends because they cannot gain the trust of their veterans; this is where I as well as veteran organizations come in, first to gain their full trust as one veteran identifying and relating to another veteran and, second, in an advocacy role to guide them through a cumbersome, not-so-easy to understand and navigate VA application, review and approval process for disability compensation and healthcare. Remember now, the Vietnam veterans were undeservingly rejected, despised or ignored by a divided American public, and it took the U.S. Congress 16 years after the end of war to acknowledge certain cancers and other diseases as caused by Agent Orange in the Agent Orange Act of 1991. Now that the University of Pennsylvania/Novartis collaboration has delivered the first FDA approved CAR-T therapy for the treatment of relapsed or refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL), I’m interested to find out, if a therapy for older adult patients is in the works that could benefit Vietnam War veterans with chronic B-cell leukemias. I also target veterans suffering PTSD and assist Iraq and Afghanistan War veterans to realize their full benefits, including surviving spouses and children.
Regards,
Ray