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Martin Karplus, Chemist Who Made Early Computers a Tool, Dies at 94

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Martin Karplus, Chemist Who Made Early Computers a Tool, Dies at 94

Martin Karplus, a Nobel Prize-winning theoretical chemist who used computers to model how complex systems change during chemical reactions, a process that has led to advances in the understanding of biological processes, died on Dec. 28 at his home in Cambridge, Mass. He was 94.

His wife, Marci Karplus, said he died while recovering from a fall in which he broke a femur.

Over his long career, Dr. Karplus had crossed paths with some of the most important scientists of the 20th century, including Linus Pauling and J. Robert Oppenheimer.

Scientists can control the chemicals in a reaction, and they can measure and evaluate the results, but what happens in between is a mystery.

As Sven Lidin, chairman of the Nobel selection committee explained when announcing the 2013 winners in chemistry: “It’s like seeing all the actors before Hamlet and all the dead bodies after, and then you wonder what happened in the middle. And actually, there is some interesting action there, and this is what theoretical chemistry provides us with — the whole drama.”

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Beginning in the 1960s, when computers were only a fraction as powerful as today’s smartphones, Dr. Karplus and his fellow Nobel laureates — Michael Levitt, originally from South Africa, and Arieh Warshel, who was born in Israel — began to build virtual models of molecules to understand what happens to them during complex reactions like photosynthesis and combustion.

The models used classical Newtonian physics to predict how multitudes of atoms and molecules move during reactions, and they used quantum physics to describe how chemical bonds are broken and formed during those reactions. This type of analysis proved particularly useful in understanding biological reactions involving enzymes, the proteins that govern chemical responses in living organisms.

There was initial resistance to the scientists’ work because it was difficult for others to accept that computer models could be accurate enough or could sufficiently account for the many variables in some reactions. But by the time the Nobel Prize was awarded in 2013, that skepticism was gone.

“Today, the computer is just as important a tool for chemists as the test tube,” the academy wrote in its announcement. “Simulations are so realistic that they predict the outcome of traditional experiments.”

At Harvard University, where Dr. Karplus spent most of his career, he and his research team in 1983 created a program for simulating molecular interaction, calling it Chemistry at Harvard Macromolecular Mechanics (CHARMM). The program is available to researchers worldwide.

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In the late 1950s, Dr. Karplus made another important contribution to chemistry: He developed what is known as the Karplus equation. It makes it possible to calculate the magnitude and orientation of protons in organic compounds involved in nuclear magnetic resonance spectroscopy, allowing chemists to study the arrangements of atoms in molecules. It is now a basic part of chemistry education.

Martin Karplus was born on March 15, 1930, in Vienna into a well-off and intellectually accomplished Jewish family. He was the second son of Johann Karplus, a banker, and Isabella (Goldstern) Karplus, a hospital dietitian.

His paternal grandfather, Johann Paul Karplus, was a neurologist who discovered the functions of the hypothalamus, the crucial brain region that controls body temperature, hunger, heart rate and other vital activities. An uncle, Eduard Karplus, was an engineer and inventor. And Martin’s older brother, Robert, became a theoretical physicist at the University of California at Berkeley.

In the face of rising antisemitism in the 1930s and a few days after Nazi Germany annexed Austria in the Anschluss of March 1938, Martin, his brother, and his mother fled to Zurich and then to France, eventually arriving in Le Havre.

Martin’s father was initially imprisoned in Vienna, but he was able to join the family before they set sail for New York. They arrived on Oct. 8, 1938, and soon after moved to Newton, Mass.

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At Newton High School, Martin discovered that his older brother had made such a mark there that many teachers doubted Martin’s ability to do as well, he recalled in a Nobel biography. One teacher, who was in charge of the Westinghouse Science competition, the nation’s top talent search in the sciences, told Martin that it would be a waste of his time to enter.

But he found another teacher who was willing to proctor his test for the competition. He went on to qualify as one of the country’s 40 finalists. Martin’s project on alcids, an aquatic bird, was chosen as the co-winner of the competition, after which he met President Harry S. Truman in Washington.

Accepted to Harvard University, he concentrated on chemistry and physics. As he was finishing his undergraduate degree in 1950, both the University of California at Berkeley and the California Institute of Technology, known as Caltech, accepted him for graduate studies.

Unsure where to go, he visited his brother, Robert, who by then was working at the Institute for Advanced Study in Princeton, N.J. Robert showed him around, introducing him to Albert Einstein and J. Robert Oppenheimer, who had led the Manhattan Project that developed the atomic bomb and who had become the institute’s director. Dr. Oppenheimer recommended Caltech, where he had been a professor, calling it “a shining light in a sea of darkness,” according to Dr. Karplus’s biography. Decision made.

At Caltech he focused on biophysics, joining a graduate group led by Max Delbrück, who, along with Salvador E. Luria, had proved that Darwin’s theory of evolution also applied to bacteria. They, along with Alfred D. Hersey, would be awarded the Nobel Prize in Physiology or Medicine in 1969 for their work.

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As Dr. Karplus wrote in his Nobel biography, a turning point in his life came two months after he started at Caltech. Dr. Delbrück suggested that Dr. Karplus present a seminar on his intended area of research: how vision works.

He began his presentation, but after 10 minutes Dr. Delbrück interrupted him to say that he did not understand what Dr. Karplus was saying. Dr. Karplus began anew, and Dr. Delbrück interrupted again, saying he still did not understand. Dr. Karplus began again, and Dr. Delbrück interrupted a third time.

At this point, Dr. Richard Feynman, who was awarded the Nobel Prize in Physics in 1965 and who was sitting in the audience, turned around and said to Dr. Delbrück: “I can understand, Max. It is perfectly clear to me.” Dr. Delbrück turned red and stormed out. Later that day, he called Dr. Karplus to his office and told him that he could no longer work with him.

Dr. Karplus switched to chemistry.

In the chemistry department, Dr. Karplus initially worked with Prof. John Kirkwood, but then Dr. Kirkwood left for Yale University. His graduate students were given the chance to switch to working with Linus Pauling. Only Dr. Karplus accepted.

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Dr. Pauling was on the short list of the greatest scientists of the 20th century. He was one of only five people to receive two Nobel Prizes: the first in 1954 for chemistry, for determining how atoms are chemically bound in molecules; and the second, the Nobel Peace Prize, in 1962, for promoting nuclear disarmament. His scientific work led to the founding of quantum chemistry and molecular biology.

Dr. Karplus’s time with Dr. Pauling proved fruitful: He finished his doctoral dissertation just before Dr. Pauling departed on a trip in late 1953. Dr. Karplus, who had received a National Science Foundation postdoctoral fellowship, then left to spend two years at Oxford University.

In 1955, he was hired by the University of Illinois, which was doing advanced work on nuclear magnetic resonance (NMR) spectroscopy. It was during his five years in Illinois that he put together his Karplus equation.

In 1960, Dr. Karplus was hired to be a researcher at the IBM Watson Scientific Laboratory and to teach at Columbia University. With access to state-of-the-art computing power, he continued his research on NMR and also began to investigate creating models to explain chemical reactions.

Dr. Karplus changed jobs again in 1966, returning to Harvard. There he started to concentrate on biological reactions, which are the most complex. The work would lead to the creation of CHARMM and to his Nobel Prize.

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In the 1990s, Dr. Karplus was appointed a professor at Louis Pasteur University, later renamed the University of Strasbourg, in France. He spent the next 20 years going back and forth between there and Harvard.

Dr. Karplus met Marci Hazard at Harvard, where she has worked for 51 years. They married in 1981. His first wife was Susan Karplus; their marriage ended in divorce.

In addition to his wife, he is survived by two children from the earlier marriage, Reba and Tammy; one child from his second marriage, Mischa; and one grandchild. (Susan Karplus died in 1982. His brother, Robert, died in 1990.)

In 2020, Dr. Karplus published his autobiography, “Spinach on the Ceiling: The Multifaceted Life of a Theoretical Chemist.” The title referred to the landing spot of a launched spoonful of spinach that he had been ordered to eat as a boy.

Over his career, Dr. Karplus supervised close to 250 graduate and doctoral students, most of whom have gone on to successful academic careers. They are collectively known as Karplusians.

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Senators Press Marty Makary on Abortion Pills and Vaccines

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Senators Press Marty Makary on Abortion Pills and Vaccines

At a confirmation hearing for Dr. Marty Makary on Thursday, senators focused heavily on the safety of the abortion pill, with Republican lawmakers urging him to restrict access and Democratic lawmakers demanding that he maintain its current availability.

Dr. Makary, President Trump’s nominee to lead the Food and Drug Administration, signaled that he shared Republicans’ concerns about the current policy, issued during the Biden administration, which expanded access by allowing people to obtain the pills without an in-person medical appointment.

Several Democrats pointed to volumes of studies showing that the drugs are safe. Dr. Makary told members of the Senate health committee, which held the hearing, that he would review the pill’s safety and the policy at issue.

He said he would “take a solid, hard look at the data and to meet with the professional career scientists who have reviewed the data at the F.D.A. and to build an expert coalition to review the ongoing data, which is required to be collected.”

The hearing also touched on vaccines, with several lawmakers, including the committee chairman, Senator Bill Cassidy, Republican of Louisiana, questioning why an advisory committee meeting on next year’s flu vaccine had been canceled in recent weeks and asking whether it would be held later. He and others stressed that the flu panel met annually, and some reminded Dr. Makary that Robert F. Kennedy Jr., who oversees the F.D.A. as health secretary, had pledged transparency in agency decision-making.

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Senator Patty Murray, Democrat of Washington, called the cancellation “unprecedented and dangerous” after decades of annual meetings.

Dr. Makary repeatedly reminded senators that he was not responsible for scrapping the meeting. He also suggested there was a need for a broader review of the role of vaccine committees that convene experts to advise the F.D.A. He shot back at criticism, saying there is a “huge difference” between “requiring every 12-year-old girl to get an eighth Covid booster” and “rubber stamping” the vaccine chosen by a global health panel that had targeted dominant influenza strains.

He offered no details about any school or entity that requires children to have annual Covid boosters.

He also was questioned about the measles vaccine in light of the current outbreak in Texas, where one child has died and 22 people were hospitalized.

“Vaccines save lives,” Dr. Makary said. “I do believe that any child who dies of a vaccine-preventable illness is a tragedy in the modern era.”

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But he did not take the bait lobbed by Senator John Hickenlooper, Democrat of Colorado, who criticized Mr. Kennedy’s endorsement of vitamin A and cod liver oil as remedies for measles. Dr. Makary responded by saying that supplements can improve conditions like malnutrition, which is associated with poor outcomes in measles outbreaks.

Lawmakers also warned about staff cuts and hiring freezes the Trump administration has ordered and how they could affect workers who inspect the safety of the food supply, and urged Dr. Makary to review the layoffs among those staff members whose salaries are backed by industry fees.

They also touched on work related to chemicals like dyes in the food supply, an area Dr. Makary agreed to study, invoking European products with fewer additives as an area for review.

Among other issues raised during the hearing, the vexing problem of illegal vape products from China with unknown ingredients was stressed by Senator Ashley Moody, Republican of Florida.

The vapes tend to have high levels of nicotine, advertise thousands of puffs and come in flavors like strawberry lemonade that are appealing to adolescents.

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Ms. Moody said it was concerning that the products were banned within China.

“Whoever comes in as the head of F.D.A., this is one of your problems you have to address immediately,” said Ms. Moody, who was previously Florida’s attorney general.

Blocking the flow of the unauthorized vapes has been a priority for major tobacco companies that have followed F.D.A. rules and marketed vapes in tobacco or menthol flavors in the United States. It’s a priority public health groups also share. Dr. Makary said he would address the problem with the F.D.A.’s law enforcement division and the Justice Department.

Throughout the hearing, several senators returned to the abortion pill and the F.D.A.’s oversight of policy changes during the lengthy history of medication abortion over more than two decades.

Mifepristone — part of the standard two-drug medication regimen now used in nearly two-thirds of abortions — has become a focal point of anti-abortion efforts since the Supreme Court overturned the national right to abortion in 2022.

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In a lawsuit filed against the F.D.A. and other efforts, abortion opponents have demanded that the agency either withdraw approval for mifepristone or roll back regulations to prevent abortion pills from being prescribed by telemedicine and mailed to patients.

The Biden administration waived the in-person dispensing requirement in 2021. Senator Maggie Hassan, Democrat of New Hampshire, said that she was concerned that Dr. Makary would “unilaterally overrule the data that currently exists for political purposes and for political reasons.”

Dr. Makary repeated that he had no preconceived notions and would examine the data. “I wish you were hedging a little bit less today,” Ms. Hassan shot back.

Mifepristone, which blocks progesterone, a hormone necessary for pregnancy to develop, has long been regulated by the F.D.A. under an especially strict program that applies to only a small number of drugs.

For years after its approval in 2000, mifepristone could be prescribed only by a doctor and patients were required to attend three in-person doctor visits to obtain and take the medication. In 2016 and 2021, based on updated scientific evidence, the agency made several changes, including that nurse practitioners and some other health care providers could prescribe mifepristone and that patients did not have to pick up the medication in person.

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Senator Josh Hawley, Republican of Missouri, argued that the policy change to drop the requirement for in-person appointments was made in anticipation of the Supreme Court decision that overturned Roe v. Wade.

Reproductive health experts and organizations, however, had long argued that the requirement was unnecessary for safety and noted that the F.D.A. had already allowed women to take the medication at home without being supervised by a doctor. The Covid pandemic increased the importance of allowing people to obtain the pill by mail because many patients were not able to visit clinics or abortion providers.

Pressed further by Mr. Hawley, Dr. Makary signaled that he shared the concerns of some abortion opponents and said that he knew doctors who preferred to give the drug in their office: “I think their concern there is that if this drug is in the wrong hands, it could be used for coercion,” he said.

Mr. Cassidy closed the hearing with a direct request: to change the policy back to what it was in the first Trump administration and require an in-person visit.

The F.D.A. has a staff of about 18,000 and a budget of about $7.2 billion. The agency has vast regulatory authority over products that include prescription and over-the-counter drugs, medical devices, tobacco and about 80 percent of the food supply. It also regulates artificial intelligence software used to scan medical images, an area where the agency has been dismissed as too permissive in its approvals.

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If confirmed, Dr. Makary would first encounter tensions among staff members, who have been whipsawed by the Trump administration’s aggressive measures to reshape the federal bureaucracy in recent weeks.

The staff endured an initial round of about 700 layoffs, decimating some product-review teams that ensure the safety of medical devices such as surgical robots and systems that deliver insulin to people with diabetes. Those firings were followed by some job reinstatements, though many of those in the tobacco division who review the safety of new products and lost their positions, were not called back.

Asked about the layoffs, Dr. Makary said he supported efforts to increase efficiency and that he would review recent personnel decisions.

Pam Belluck contributed reporting.

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Contributor: How federally funded research saved my son's sight — and his life — from a rare cancer

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Contributor: How federally funded research saved my son's sight — and his life — from a rare cancer

If you want to make this country great, imagine the strength of a nation whose children have been fought for and know they have been fought for.

Last month, my son reached two years in remission from a rare, malignant cancer that almost took his eye and his life. He is alive, well and enjoying 20/20 vision because of a groundbreaking treatment that was pioneered by National Institutes of Health researchers, among others, and funded by the government grants the Trump administration is blocking and threatening to cut. If the president continues on this course, children diagnosed during and after this administration will needlessly fare worse than those who came before.

My son Jack was diagnosed in 2022 with retinoblastoma, a malignant childhood cancer of the central nervous system that originates and grows in the eye. If left untreated, it typically migrates through the optic nerve to the brain, eventually metastasizing and taking the life of the child.

Because the cancer usually attacks children under the age of 3, its victims are often unable to report the symptoms of a mass blocking their vision until it’s too late to treat with procedures that can salvage the eye. That’s when enucleation — removal of the eye — is required.

This is why pediatricians developed standard screening for retinoblastoma starting at birth. This now-routine preventative care has enabled medical professionals to find and treat most cases without a loss of vision or life. Because of these developments and others, retinoblastoma has a very high survival rate in 21st century America.

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Jack’s was one of very few documented diagnoses with retinoblastoma after the age of 8. His oncologist suggested his tumor had been hiding in a dark corner of his retina for years, out of his vision and that of physicians; other doctors thought it had “self-arrested” or presented late and grew rapidly. We discovered it only because it burst from the impact of a belly flop at the neighborhood pool, spewing cancer cells in a constellation of poison floating inside his still-intact eyeball, visible to Jack as spots that didn’t go away.

It took weeks for doctors to nail down the diagnosis. When we walked out of that appointment on a day that was so windy I had to hold onto my dress, I put Jack in the car, turned the radio on for him, closed the passenger door and walked about 30 feet away to scream in the parking lot. “My baby!” I wailed through the phone to my mother.

It was an advanced-stage tumor, complicated by the release of cancer cells inside his eye. They could now attach and grow anywhere within — including the optic nerve, with its direct connection to his brain — if we didn’t act quickly. We might have just days before it was too late.

“We could remove his eye,” our oncologist offered at first, “and even that might not be enough.”

Medical researchers from universities and the National Institutes of Health rally near the Health and Human Services Department’s headquarters in Washington.

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(John McDonnell / Associated Press)

Then he explained that we could try to save his eye with a highly advanced procedure called intra-arterial chemotherapy, or IAC. It involves threading a catheter through the thigh’s femoral artery, behind the heart through the carotid artery and into the skull. An interventional radiologist, guided by MRI, releases the chemotherapy agent directly into the artery feeding the retina. This allows doctors to deliver more aggressive and targeted medicine to the diseased cells and limit damage to the healthy ones.

Our oncologist explained that IAC is still a very new technology but one with extraordinary promise whose benefits far outweighed the risks for Jack.

My son underwent six rounds of intra-arterial chemotherapy and seven rounds of intravitreal chemotherapy, in which the medicine is injected directly into the eye. He went under anesthesia 13 times in six months, required monthly breathing treatments that made him spit gray foam, and lost most of the brow and all the lashes around the affected eye. His list of drugs included ketamine, propofol, hydromorphone, melphalan, fentanyl, topotecan, pentamidine, albuterol, prednisolone and aldosterone. At one point, he needed epinephrine because he nearly went into cardiac arrest. Toward the end of his treatment, he received cryotherapy to kill the base of the tumor and woke up from surgery in so much pain that he gritted his teeth to the point of cracking one.

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At every turn, my family was reminded of our privilege — to live in a country that was scientifically advanced enough to have developed such miracle treatments, to live in a city (Denver) with such good hospitals, to have good health insurance through my husband’s employer. If we had lived without such access to care, in a country lacking our resources or just 15 years earlier, our story would have ended differently. Instead, nine months after his diagnosis, thanks to the advanced research our country has supported socially, academically and financially, my son’s cancer was in remission.

My family recently attended a gathering with other retinoblastoma survivors, from toddlers to adults who had conquered the disease decades earlier. As each survivor entered the conference, it became evident that this was once primarily a disease of blindness: The price of survival was generally a loss of sight and eyes. Some of the older survivors had facial abnormalities from radiation or enucleation. Some had canes or family members to guide them. When we told the group that Jack’s body, vision and dream of becoming a pilot were all still intact, many gasped in awe that the science had advanced so far.

But now the Trump administration’s lack of empathy threatens other children and families facing such horrific diagnoses. Continuing research on intra-arterial chemotherapy and other treatments at the University of Colorado’s Anschutz Medical Campus, where Jack was treated, is paid for by programs in the administration’s crosshairs. “These cuts to NIH funding jeopardize the foundation of our life-saving research,” a university spokeswoman told Chalkbeat Colorado. “Reduced research capacity means fewer scientific discoveries, job losses and delayed advancements on therapies and cures that could improve — and save — lives.”

I wonder whether our hospital will be able to continue offering groundbreaking treatments should Jack face a recurrence. And will the newly diagnosed have the same access to care that we did? What greatness can be celebrated when a mother fears she will lose her child’s access to lifesaving treatment?

My son’s recovery was a direct result of the greatness of our country and its past leaders, who had the foresight to pursue progress and excellence in science and refuse to accept losing children without a fight. Because of it, I believe my son will someday fly planes. And I can only hope the next child who faces a dire disease will get the same chance he did.

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Dayna Copeland is a writer and teacher in Colorado.

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Florida Seeks Drug Prescription Data With Names of Patients and Doctors

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Florida Seeks Drug Prescription Data With Names of Patients and Doctors

Florida’s insurance regulator has demanded an unusually intrusive trove of data on millions of prescription drugs filled in the state last year, including the names of patients taking the medications, their dates of birth and doctors they’ve seen.

The Florida Office of Insurance Regulation in January sought this information from pharmacy benefit managers like UnitedHealth’s Optum Rx and CVS Health’s Caremark, companies that oversee prescription drugs for employers and government programs.

It remained unclear why the state was ordering the submission of so much data. In a letter to one benefit manager reviewed by The New York Times, the regulator said the state required the data to review whether the benefit managers, known as P.B.M.s, were compliant with a 2023 state law aimed at lowering drug prices and reining in the managers.

But the demand is sparking concerns about government overreach and patient privacy.

“You don’t need such granular patient information for purposes of oversight,” said Sharona Hoffman, a health law and privacy expert at Case Western Reserve University. She added: “You have to worry: Is the government actually trying to get information about reproductive care or transgender care or mental health care?”

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Florida’s six-week abortion ban, enacted by Gov. Ron DeSantis, a Republican, and the state’s Republican-dominated legislature, requires that doctors who prescribe abortion pills dispense them in person, not through the mail. Another Florida law banned transgender transition care for minors and made it harder for adults to seek such care. Last year, a judge struck down key parts of that law, though it is still being enforced while the legal fight makes its way through the courts.

The data requested by the state could, in theory, be used to determine whether physicians are complying with those laws.

It was also unclear whether any of the benefit managers had complied and turned over the information to the state.

Some benefit managers and the employers that hire them to handle prescription drug benefits for their workers have also criticized the state’s demand.

A group of large employers, the American Benefits Council, is asking the Florida regulator to withdraw its order to turn over the information. In a letter to the state, the council’s lawyers wrote that the “demand impermissibly violates the health privacy and security of millions of Floridians,” and that the state had not clearly outlined its authority or reasons for the action.

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“We have a duty to employees and their data,” Katy Johnson, the president of the council, said in an interview.

Shiloh Elliott, a spokeswoman for Florida’s insurance regulator, said that objections to the state’s data request “are clearly from those who do not want to be regulated or have any oversight in their industry.” She said the office “will continue to request data in the best interest to protect consumers.”

Rosa Novo, the administrative benefits director for Miami-Dade County Public Schools, which provides health coverage to about 45,000 people, said in an interview that while she appreciated the state’s efforts to address drug prices, it was unclear why it would need this level of detailed information about patients and their medications.

“My doctor is the only one who should know that,” Ms. Novo said.

Federal privacy law allows benefit managers to hand over limited data about individual patients in certain circumstances, such as when regulators are conducting an audit. But, according to experts, Florida’s data request could violate the law because it is so broad and may go beyond what the regulator needs to conduct its review.

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Experts said that another concern with Florida’s request is that when sensitive patient data is in multiple hands, it raises the risk of a breach in which the information may be stolen.

Ms. Elliott, the spokeswoman for the regulator, said those concerns “should be addressed to the actual health care insurance companies that have had countless data breaches exposing millions of Americans’ sensitive information.”

Florida’s data order was first reported by Bloomberg.

Like other states, Florida already has access to some of the data it is seeking, such as detailed information about prescriptions that are paid through Medicaid. But that data is generally strictly walled off, accessible only to staff members whose jobs require it.

Benefit managers often field requests from government regulators asking for slices of data to conduct audits or investigations. Such requests typically ask benefit managers to strip out patient names, and other identifying details, or ask for a small sample of patient claims.

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By comparison, Florida’s data request was “pretty expansive and unprecedented,” said Joseph Shields, the president of a group of smaller benefit managers, Transparency-Rx.

Florida sought data not only on Florida residents, but also on patients who may have filled a prescription while visiting the state. Its request included patients covered through the federal Medicare program and commercial plans through employers that are regulated under federal law rather than state law, according to the regulator’s letter to one benefit manager reviewed by The Times.

The Prescription Drug Reform Act, the Florida law the regulator used to justify the data request, imposed new reporting requirements on the benefit managers but said nothing about a mandate requiring them to turn over such detailed patient information. Benefit managers have fiercely fought efforts to scrutinize their business practices.

Patricia Mazzei contributed reporting from Florida.

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