The process of developing new cancer drugs and bringing them to the market needs a major overhaul, argued distinguished futurist Vivek Wadhwa in an email to colleagues and friends the day after he lost his wife to a rare form of cancer called cholangiocarcinoma.
Wadhwa is known for his ideas on the future of everything from artificial intelligence and driverless cars to the relationship between immigration and technology. He has authored thought-provoking books, including "Your Happiness Was Hacked: Why Tech is Winning the Battle to Control Your Brainand How to Fight Back," and is a contributor to the Washington Post, Bloomberg BusinessWeek, and Forbes, among other national media outlets. As one of TIME magazine’s "Forty Most Influential Minds in Technology," a Distinguished Fellow and professor at Carnegie Mellon University Engineering, Silicon Valley, and Distinguished Fellow at Harvard Law School's Labor and Worklife Program, Wadhwa's words carry weight among futurists worldwide.
Read More"The doctors who were helping Tavinder are the best of the best and we had access to the most advanced medical technologies," Wadhwa wrote. "The reason we could not win this battle, as I learned, is that our medical system is stuck in the dark ages."
Which Drugs Would Have Worked? Wadhwa Argued That They Could Have Had the Answer Sooner
The cancer that took Tavinder's life, cholangiocarcinoma, is a cancer of the bile ducts, a series of tubes that carry a liquid called bile between the liver and the small intestine, where it plays a crucial role in digestion. The cancer is only diagnosed in about 8,000 people in the U.S. each year, and has a five-year survival rate of six percent once it has spread beyond the bile ducts to other parts of the body, as it had in Tavinder's case.
After her diagnosis, Tavinder initially received a standard regimen of chemotherapy, which had side effects that Wadhwa described as "debilitating." The chemo did not stop the cancer from progressing, though, and so, as Wadhwa shared in his email, Tavinder and her doctors took the next step of trying to find her a clinical trial based on her tumor's genetic makeup. Tavinder enrolled on a clinical trial for a new targeted treatment drug called ivosidenib that targets an IDH1 gene mutation (which genetic sequencing determined was present in Tavinder's tumor). The drug showed promise initially, but ultimately could not stop the cancer from progressing either.
After trying one more chemotherapy regimen after the unsuccessful clinical trial, Wadhwa wrote, "We were about to try a new set of drugs which would likely have healed her, but her body gave in."
Patient-Derived Organoids
Wadhwa's argument about the too-slow pace of medical innovation was based largely on the notion that existing technology could have informed doctors right-off-the-bat that the drugs Tavinder tried wouldn't work, and that the new set of drugs Tavinder was about to try would. "Yet by the time we procured the drugs, Tavinder had run out of time," he wrote. "She had endured more than enough and her heart and liver failed."
The technology Wadhwa was referring to is a way of testing treatments on living samples of patients' cancer tumors outside of their body, called "patient-derived organoids" (PDOs).
Using PDOs, doctors can test new drugs on cancer cells that have been taken from tumors and kept alive outside of the bodyand they can do so before testing these drugs in the person.
On its site, the tumor sample-managing company SpeciCare, through which Wadhwa was first introduced to a lab that would test treatments in Tavinder's tumor sample, explains "We now know living tumor tissue may be the key to unlocking new personalized treatment options and revelations in cancer care that were not previously available. By saving and preserving tumor tissue alive, we can offer individuals a new and important validation step to eliminate ineffective therapies and to identify effective therapies more quickly opening the door to significant opportunities for long-term survival."
Through SpeciCare, Wadhwa and Tavinder found the PDO testing lab, SEngine Precision Medicine. A month before Tavinder died, Wadhwa said that the lab created an organoid her tumor, tested this with 135 cancer drugs, and accurately predicted that all three treatments she had already received would be "sub-optimal" for her cancer. Instead, the tests showed that Tavinder's tumors would have responded best to a drug called a MEK inhibitor, which they "had not considered because of the availability of clinical trials."
As soon as they had this knowledge, doctors started Tavinder on a MEK inhibitor called trametinib, and Wadhwa shared that within 10 days, some of her tumors had astonishingly shrunk. But trametinib was ultimately too strong for Tavinder with its side effects, so the researchers developed three different combinations of MEK inhibitors that Wadhwa said "may have treated the cancer and bought time for the cure." But because the tumor sample tests and subsequent developments all happened too late to save Tavinder, Wadhwa wrote, "I have lost the most important person in my life."
Uptake Requires Incentive
In Wadhwa's message, he argued, "there are hundreds of research labs all over the world using these [PDOs] yet they are not actively used in the field, largely because of ignorance and motivation."
While ignorance (not knowing about how to conduct PDO tests) and motivation (being motivated to do things the old way by a drug approval or profit) could indeed be a reason why PDOs aren't widely used, there may be other other factors that play into slow uptakeincluding the need to test drugs in living humans to know about how they effect the body at-large, not just the tumor. Cost, knowledge of how to conduct these tests, and the fact that the U.S. Food and Drug Administration (FDA) requires human trials for drug approvals all play into the reason PDOs are not widely used today.
But Wadhwa's argument was less about whether it would be realistic or beneficial to implement the technology on a wide scale and more about the fact that the system of new drug development is too set in its waysand its profit-driven incentivesto entertain the idea.
"Technology has now progressed to the point that we can cure almost every disease," Wadhwa wrote. "However, we do things the way as a century ago, with a system geared to meet the needs of the pharma companies and appease regulators. Patients audition for clinical trials with drugs and dosages formulated to maximize chances of FDA approval and one-third or more receive placeboswith the rest having a slim chance of being cured."
“You either embrace the technology or you become it’s casualty”, says Vivek Wadhwa @wadhwa #PayCon #AI, #Robotics pic.twitter.com/9oKv02MXSU
Neeyamo, the HRO (@Neeyamo) May 16, 2019
“You either embrace the technology or you become its casualty,” Wadhwa said in a presentation in May. While he wasn’t speaking about medicine at the time, the argument mirrors the one he makes about drug development today.
Medicine is Complicated; There is Always a Flip Side
We've heard from many experts in the past that there's a good reason the process of developing new drugs and getting them to the market is so slow; the strict protocols and rigorous levels of testing ensures that drugs will work (and work safely) in the widest possible net of patients they're supposed to treat.
"From the societal standpoint, we really cannot understand whether these therapies work without subjecting them to rigorously controlled trials," Dr. Ben Neel, Director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, recently told SurvivorNet.
And hurdles along the way that further slow the process, such as struggling to recruit enough participants for clinical trials, often stem from protocols designed to make trial results more accurate.
Dr. Alana Welm, Associate Professor in the Department of Oncological Sciences at the University of Utah, and an investigator and co-leader of the Cell Response and Regulation Program at the Huntsman Cancer Institute, for instance, previously explained to SurvivorNet why some patients are excluded from clinical trials. "If we were to do a trial where we didn’t have certain inclusion criteria or certain exclusion criteria, the result would not be interpretable," she said.
But many patients, doctors, and patient advocates have argued that these exclusion criteria can be too strict, and are part of the reason why so many clinical trials do not meet their enrollment goals (and therefore cannot proceed.)
And even post-FDA approval, doctors don't always change the way they practice right away. Some oncologistsespecially those who have been in the field for decades and have firmly established protocols for treating patientsmay be slow to adopt completely new paradigms.
"Nationally, most people wait until experts agree that evidence is strong enough to change guidelines," Dr. Heather Yeo, associate professor of Surgery and Healthcare Policy and Research at Weill Cornell Medical College, and assistant attending surgeon at NewYork-Presbyterian/Weill Cornell Medical Center, previously told SurvivorNet. "And actual practice can lag a little because one small study shouldn't necessarily change an entire practice."
What’s Next For PDOs and the Future of Drug Development?
That’s a big questionand one that we’re keeping close tabs on here at SurvivorNet, while discussing PDOs with experts who can weigh-in on their use.
But however complicated the specific technology of PDOs and its uptake may be, Vivek Wadhwa's baseline messagethat the medical field and research system needs to break the habit of doing things the way they've always been done simply because that's the way they've always done themis a universal enough message to get behind: to save lives, we need innovation, and to achieve innovation, we need open minds.
"I am sharing all this with you so that you can learn from my experiences and leapfrog the process for other patients you may know," Wadhwa concluded his email. "Tavinder said that if her suffering would help prevent the suffering of others, it would be worth it. She also instructed me to spend the rest of my life helping othersand that is what I plan to do."
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