A cutting-edge treatment for blood cancer in children with promising short-term remission rates has nevertheless come under intense scrutiny due to its unprecedented cost.

Acute lymphoblastic leukemia (ALL) is the most commonly diagnosed pediatric cancer. Though treatment advances have driven five-year survival rates above 90 percent, relapse is common and ALL remains a leading cause of death from childhood cancer. Those surviving relapse typically require hematopoietic stem cell transplant (HSCT) to remain in remission.

The Food and Drug Administration last year approved tisagenlecleucel as the first anti-CD19 CAR T-cell therapy for relapsed or refractory pediatric ALL. While tisagenlecleucel-induced remission rates are encouraging compared with those of established therapies — more than 80 percent compared with less than 50 percent — a one-time infusion costs $475,000.

That makes it one of  the most expensive oncologic therapies out there, even though no studies exist to show how the therapy maintains remission in the long term.

So Stanford Health Policy’s John K. Lin, Jeremy Goldhaber-Fiebert and Douglas K. Owens, in collaboration with Kara Davis, an assistant professor of pediatrics at Stanford’s Lucile Packard Children’s Hospital, set out to determine whether the treatment is cost-effective. 

Their study was recently published in the Journal of Clinical Oncology.

“CAR-T cells are an exciting new therapy to help us cure more patients with ALL,” said Davis. “They use a patient’s own immune system to precisely target their leukemia and remission rates are impressive for patients with relapsed disease.”

The researchers note, however, it remains unknown whether tisagenlecleucel is sufficient to cure relapsed or refractory disease without a transplant.

Not only is it a very expensive treatment, it also has expensive and serious side effects, such as cytokine release syndrome, which can cause symptoms ranging from fevers and muscle aches to lethal drops in blood pressure and difficulty breathing, requiring ICU-level care.

“Given [its] high cost and broad applicability in other malignancies, a pressing question for policymakers, payers, and clinicians is whether the therapy’s cost represents reasonable value,” the authors wrote.

In order to evaluate the economic value of tisagenlecleucel, the authors created a computer simulation that modeled children with relapsed or refractory ALL. Since the durability of the therapy’s effects are unknown, they evaluated the therapy at different levels of long-term effectiveness.

Through their analyses, the authors found that at the simulation’s most optimistic projections, patients receiving tisagenlecleucel would, on average, live over a decade longer than those receiving alternative therapies. At these projections, the therapy would be cost-effective. However, at more modest long-term outcomes, its clinical and economic benefits declined.

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“The durability of CAR-T cell therapy is the main question. For many children with relapsed or refractory ALL, their disease is fatal — if the therapy results in sustained remissions, it would represent an important advance,” said lead author Lin, who is a VA Health Services Research and Development Fellow at Stanford Health Policy.

In the end, the researchers concluded that at tisagenlecleucel’s current price, its economic value is “uncertain,” as the true cost-effectiveness depends on its long-term performance, which has yet to be determined. They noted that substantial price reductions would improve its cost-effectiveness even if its long-term performance is relatively modest.

“A commonly asked question for many expensive, novel therapies is why can’t prices be lowered at least until we know how well they work,” said Goldhaber-Fiebert. 

The “Catch-22” here is that long-term effectiveness data are needed to justify a drug’s price, but current uncertainty about its effectiveness, along with its high price, means developing the data to justify its price occurs much more slowly.

“CAR-T is an individually tailored treatment that has thus far been produced for a relatively small number of patients,” Goldhaber-Fiebert said. “Its current production costs may well be very high, and certainly the companies that have spent heavily on its research and development are interested in achieving returns on their investments.”

When the effectiveness of a therapy is uncertain, some pharmaceutical companies and health policy experts have proposed something called outcomes-based payment, which is essentially a “money-back guarantee” if the therapy doesn’t work as intended.

Novartis, which developed tisagenlecleucel, has a money-back guarantee; if the patient does not achieve initial remission within the first month, they are not responsible for the payment of the therapy.

“However, we find that because most children have an initial remission, this does not materially improve cost-effectiveness,” Lin said.

He suggested that if the money-back guarantee were extended to see whether the patient relapses within a year, such a guarantee would improve the treatment’s cost-effectiveness.

The other co-authors of the study are James I. Barnes, Alex Q.L. Robinson, Benjamin J. Lerman, Brian C. Boursiquot and Yuan Jin Tan.

The United States is in the grip of an opioid epidemic, which is affecting millions of Americans and claiming thousands of lives. Many trace their opioid dependence back to their doctor’s office, the drugs prescribed for pain after an injury, surgery, or dental procedure. Were these painkillers over prescribed? Did drug manufacturers exaggerate opioids’ effectiveness while deliberately underplaying their danger? Did drug distributors and retailers take necessary steps to ensure that pills weren’t falling in to the wrong hands?  

In this Q&A, Stanford Law Professors Michelle Mello, an expert in health law and core faculty member at Stanford Health Policy, and Nora Freeman Engstrom, an expert in tort law and complex litigation, explain the scope of the opioid problem and discuss the latest cases and legal challenges.

Just how big of a problem is the opioid crisis in the United States? Can you describe the problem’s scope and seriousness? 

Engstrom: The opioid problem is monstrous. Some 2.4 million Americans have an opioid use disorder, and the epidemic has already claimed 300,000 American lives, including 42,000 in 2016 alone. Worse, if the problem isn’t addressed, death tolls will rise: opioids are on track to claim the lives of another half-million Americans within the next decade. That’s like wiping out the entire city of Atlanta. The economic cost is also astronomical. The Council of Economic Advisors has estimated that, in 2015, “the economic cost of the opioid crisis was $504.0 billion, or 2.8 percent of GDP.”

Mello: If there’s one picture that brings home the shocking toll, it’s this one, showing trends in U.S. deaths based on data from the Centers for Disease Control and Prevention.  Nearly all of the “Poisoning” deaths shown here are opioid related. In terms of what’s killing Americans, opioids dwarf car crashes and guns.

Opioid lawsuits are now making news . Some of the actions are criminal, pursued by the states and federal government. Others of those suits are being initiated by cities, counties, and even states. What do those latter suits allege and what damages are the public plaintiffs trying to recover?

Engstrom: In the past four years, roughly 400 cities, counties, and states have initiated lawsuits seeking recovery for their additional public spending traceable to the opioid epidemic. The governmental entities claim they have been injured because defendants—typically, opioid manufacturers, distributors, and big retail pharmacies—have pumped opioids into the hands of their citizens and, in so doing, increased their spending for governmental services. Everything from policing, education, foster care, the provision of health care, even the operation of coroner’s officers, have all been made more expensive because, as compared to a healthy citizenry, an opioid-addicted populace is far less productive and needs much more by way of government help. Facing these spiraling costs, the governmental plaintiffs contend that the opioid defendants—who, they contend, caused and profited from this crisis—should foot the bill.

So, the typical defendants in these cases are opioid manufacturers, distributors, and big retail pharmacies. What is it that the plaintiffs are alleging these defendants did wrong?

Mello: There are some variations state to state, but for manufacturers, plaintiffs are typically claiming that they made false statements to prescribers and others that the drugs were safer and less addictive than alternatives, even when mounting evidence showed otherwise; that they failed to warn physicians and patients about the risks; and that the products were defectively designed—for example, because manufacturers didn’t make the pills tamper-resistant. For distributors and retailers, the claims are that these defendants failed to monitor, detect, investigate, and report suspicious orders of prescription drugs, even though reasonably prudent suppliers would have done so and the federal Controlled Substances Act requires suppliers to maintain effective controls against diversion of controlled substances to illicit markets.

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There are a billion guns in the world today. Those firearms took the lives of about 251,000 people in 195 countries in 2016, according to new research. 

That’s a lot of guns and fatalities, mostly by homicide, suicide and accidents with firearms.

About 35 percent of those gun deaths were by Americans committing suicide.

In the most comprehensive investigation of its kind, the findings, published this week in the Journal of the American Medical Association (JAMA), show 64 percent of firearm-related deaths were homicides, 27 percent were suicides and 9 percent were unintentional deaths.

And in all but one year of the 27-year study period — 1994 due to the Rwandan genocide — firearm deaths were more common along sidewalks than on the battlefields.

“This constitutes a major public health problem for humanity,” said Stanford Health Policy’s David Studdert, a professor of medicine and professor of law.

In an accompanying editorial alongside the research by a consortium of public health experts, the Global Burden of Disease 2016 Injury Collaborators, Studdert and his co-authors write:

“Injuries and deaths from firearms are increasingly part of modern consciousness, particularly in some countries. In the United States, gun-related massacres at schools, places of worship, workplaces, night clubs, and recreational venues have seared images of innocent victims in the minds of the populace. In the United States and elsewhere, acts of terrorism committed with firearms and other lethal means have changed the way people live, work, travel, and play.”

But Studdert and his co-authors — firearms and public health experts Frederick P. Rivara at the University of Washington and Garden J. Wintemute at the University of California, Davis — argue that the deaths from these headline-generating mass shootings and terrorist attacks are only a fraction of the public health burden of firearm-related murders and suicides.

“Mass shootings and terrorism perpetrated with guns are the most visible forms of firearm violence,” Studdert told SHP. “But most firearm deaths are private tragedies. They are homicides and suicides that occur behind closed doors, leaving families and communities devastated.”

The global burden of firearm mortality is highly concentrated, according to the research. In 2016, six countries in the Americas — Brazil, the United States, Mexico, Columbia, Venezuela and Guatemala — accounted for slightlymore than 50 percent of all deaths.

An estimated 32 percent of the deaths occurred in just two countries, Brazil and the United States, with Brazil accounting for one-fourth of all firearm homicides and the United States 35 percent of all firearm suicides.

“For individuals living in the United States, where the national policy debate has focused largely on interpersonal violence, the study provides a reminder of the importance of firearm suicide. In 2016, there were 2 firearm suicides for every firearm homicide, a margin that has widened over the past decade as suicide rates have increased and homicide rates have been relatively flat. Older white non-Hispanic men are at greatest risk of firearm suicide. Research and prevention efforts in the United States should proceed from a more inclusive definition of firearm violence.”

The authors believe more robust methods for estimating the number and distribution of firearms — as well as a better understanding of access — are critically important in determining which policies and prevention strategies are most effective and how best to implement them.

Studdert and his fellow researchers said research on firearm violence and public health has been impeded by the Dickey Amendment, the 1996 bill that mandated “none of the funds made available for injury prevention and control  at the Centers for Disease Control and Prevention may be used to advocate or promote gun control.”

“In the absence of this funding, several private foundations have stepped in to fill the void," they wrote. "However, real progress in addressing the vast public health problem that the Global Burden of Injury Collaborators document will depend on sustained action from governments in both research and policy.”

Federal health advisors say women can now consider three options when it's time for their cervical cancer screening tests. The influential group, the U.S. Preventive Services Task Force (USPSTF), has expanded its recommendations for this potentially life-saving exam.

The new recommendations were published in the latest issue of JAMA.

Pap smears have saved many lives since they became available decades ago. Inspecting samples of cervical tissue for pre-cancerous changes is effective at catching possible cancer, and is still the go-to test for women aged 21 to 29, according to the USPSTF guidelines. But there's another option. 

"Most cervical cancer is caused by what's called the human papilloma virus, or HPV," says Stanford Health Policy's Dr. Douglas Owens, a professor of medicine at Stanford Medicine and vice-chair of the USPSTF. "And we now have tests for HPV and that's an important step forward."

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In the summer of 2018, the Asia Health Policy Program (AHPP) at the Shorenstein Asia-Pacific Research Center (co)hosted two conferences in Beijing. From June 25-26, AHPP hosted “Healthy Aging and Chronic Disease Management in China and India in International Comparison” at the Stanford Center at Peking University in Beijing. Immediately following the event, June 26-27 AHPP cohosted, along with Professor Fang Hai, Peking University China Center for Health Development Studies, the “Fourth Annual Conference on Primary Care and China’s Health System Reform”, focused this year on China’s family doctor system.

Healthy Aging and Chronic Disease

Day one of the Healthy Aging and Chronic Disease Management conference combined discussions of chronic disease control in India and China (part of an ongoing SCPKU Team Innovation faculty fellowship) with a workshop focused on assessing net value of diabetes management across Asia.

Research teams from Hong Kong, South Korea, India, Taiwan, and the United States convened to discuss research on net value analysis of diabetes in their respective countries. The Net Value in Diabetes Management project seeks to develop a method for measuring net value of diabetes internationally­–based on previous methods discussed in an 2009 study by Karen Eggleston and Joseph Newhouse with data from the Mayo Clinic for Type 2 Diabetes.

The research teams provided updates to their calculations from the gathering last year and explained the strengths and weaknesses of their data sets, the risk prediction model they employed or created for their specific population, and the cost effectiveness analyses conducted with their data.

Participants included Kavita Singh from the Public Health Foundation of India, Janet Lam from Hong Kong University, Hongsoo Kim and Wankyo Chung from Seoul National University, Rachel Lu and Ying Isabel Chen of Chang Gung University Taiwan, and Kyueun Lee and Karen Eggleston of Stanford University.

Non-communicable/Chronic Disease Control

The afternoon of day one featured presentations by various representatives from provincial and national-level Centers for Disease Control and Prevention (CDC) in China regarding non-communicable disease (NCD) control initiatives.

Dong Jianqun from the People’s Republic of China CDC presented the “Effect of Community-Based 5+1 staged diabetes management.” This research project–fielded in sites in three different provinces–involved staged diabetes targeting management. Results showed that examination rates for complications management increased. Fang Le from the Zhejiang Provincial CDC presented updates on community management of NCDs in Zhejiang, including the intensive follow-up system for high risk diabetes patients. Representatives from Shandong University and the Shandong CDC, including Dr. WANG Yan, presented “The Status, Problems, and Determinants of community management and control of diabetes in Shandong Province” while also discussing current policy and implementation.

The afternoon ended in a session comparing health care systems and ongoing initiatives for chronic disease control in China and India. Kavita Singh discussed issues in India’s health system, including high out of pocket expenditure, over-privatization, and large health inequities across states and between urban and rural areas. Singh introduced existing innovations being used, including smartphone-based decision support software in heart disease monitoring. Dong Jianqun and colleagues discussed NCD control in China, including the demonstration areas that have integrated initiatives including better surveillance and management of diabetes and hypertension, and prevention education.

The first conference closed the next morning by bringing together representatives from various Chinese organizations to discuss the current state of primary care, family doctor system, and health care reform within the country. During a highly immersive classroom session for the Diabetes Net Value Teams, Dr. Sanjay Basu shared insights regarding best practices in predictive risk modeling.

China’s Family Doctor System

Beginning the afternoon of June 26, the second conference was devoted to China’s family doctor system, primary care, and health care reforms.  The event opened with remarks from Zhuang Ning, Deputy Director of the State Department of Health, System Reform Department, about the importance of community health and greater recognition of primary health providers in China.

The director’s remarks were followed by an opening keynote address by Professor MENG Qingyue, Dean of the Peking University School of Public Health and Director of the China Center for Health Development Studies at Peking University. Professor Meng reflected on the role of primary care in the development of China’s health system. Qin Jiangmei, Director of the Community Health Research Center, National Health and Family Planning Commission Health Development Research Center, next introduced the necessity of comprehensive health reform in China as well as funding challenges.

Afterwards, representatives from the Beijing Dongcheng district, Shanghai Changning district,  Xiamen City, and Shenzhen Luohu Hospital Group shared their experiences constructing family doctor systems within their respective regions. Important points stressed by the presenters included consolidation, maintaining a good evaluation system, and establishing trust with their patients.

The day ended with a Primary Medical Care Roundtable Discussion featuring four directors of district-level community health centers. The panelists answered questions concerning the future model of primary care in China, as well as changes they would like to see at the community and policy levels. The district directors advocated that more funds be allocated to general practitioners, believing that they will be the dominant form of primary care in China. Participants also spoke of the additional need for clearer targets to ensure that primary care providers are better funded (so that, with enough time, patients will begin to recognize the importance of the family physician).

The second conference concluded on June 27 by way of a highly engaging classroom session on the continuing collaboration between the Zhejiang Provincial CDC and Stanford University Asia Health Policy Program.