Clinical Trials

Introduction

Richard Vinci, 51, an engineering professor at Lehigh University, is participating in a clinical trial for treatment of amyotrophic lateral sclerosis, or Lou Gehrig's Disease, at Massachusetts General Hospital in Boston. It is the first late-stage U.S. trial to determine if stem cells harvested from bone marrow, modified and then injected into spinal fluid, will halt or slow the fatal disease. (Cover: Getty Images/The Boston Globe/David L. Ryan)

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Overview

Doctors diagnosed Carly Bastiansen with advanced pancreatic cancer in January 2016 and told her she would not survive long with standard treatment. So the 29-year-old children's librarian in Baltimore spent more than a year applying to six clinical trials testing experimental drugs against the aggressive disease.

Each time, Bastiansen failed to meet the trial's eligibility criteria, however. In one case, lab tests showed her liver function as just outside the normal range, so she was deemed too sick to participate. “Participating in a clinical trial is really my only chance at living longer,” she told The Washington Post after her fruitless search. “To have had that option taken off the table was devastating.”1

Bastiansen died last November.

Clinical trials are designed to answer questions about the safety and efficacy of drugs, medical devices, vaccines and behavioral therapies, everything from hip replacements to the latest immunotherapies for cancer. The U.S. Food and Drug Administration (FDA) relies on data from trials when deciding whether to approve new medical interventions or new uses for existing treatments. Industry, government agencies, universities and nonprofit groups sponsor trials, which are often conducted by physician-researchers at medical institutions and other research sites. Drug and medical device companies are the largest funders, by far.

Carly Bastiansen, 29, a children's librarian from Baltimore, was diagnosed with advanced pancreatic cancer in January 2016. She tried to get into six clinical trials testing experimental drugs against the disease but failed to meet any trials' eligibility criteria. She died last November. Some doctors and advocacy groups argue that eligibility criteria are overly narrow and partly to blame for the persistently low participation rates for clinical trials. (Courtesy David Bastiansen)

Eligibility criteria, such as limits on age, severity of disease and overall health, are meant to decrease the likelihood of harm to trial participants. They also ensure that participants are enough alike so researchers can say with confidence that any benefits or harms experienced during the trial are due to the experimental therapy and not to patients’ differences or unrelated health conditions.

But some doctors and advocacy groups argue that eligibility criteria are overly narrow and are partly to blame for the persistently low participation rates for clinical trials. Less than 5 percent of Americans ever enroll.2 Among other reasons given: not knowing about a trial, fear of being a “guinea pig,” geographic barriers and the lack of an appropriate trial for their disease or condition.3

The low participation rate create serious consequences: Nineteen percent of clinical trials registered in a government database were closed before they could begin or terminated early because they could not recruit enough participants, and up to 86 percent of trials experienced significant delays because it took so long to reach recruitment goals, according to a 2015 analysis. Critics also say trial sponsors do not always reveal negative results, while stakeholders across the spectrum say trials have become too complex and costly and minorities and the elderly are underrepresented.4

“Our ability to meet urgent medical needs is at stake,” said Barry Getz, the former head of clinical trials at Merck, a pharmaceutical company based in Kenilworth, N.J. “These needs range from the ability to fight newly emerging, highly virulent infections such as antibiotic-resistant bacteria … to the population's increasing afflictions, which include chronic disease … and finally, to scourges of the aging — most notably [Alzheimer's] disease.”5

But patient groups, clinicians, medical institutions, device makers and drug companies, which can range from small biotechnology firms to pharmaceutical conglomerates, do not necessarily agree on what needs to be done.

Several groups are trying to find solutions. For example, the Clinical Trials Transformation Initiative (CTTI), an organization in Durham, N.C., that works to improve the quality and efficiency of clinical trials and whose members include patient advocacy groups, professional societies, academic institutions and representatives from industry and government, is encouraging trial sponsors to involve patients in designing clinical trials to make them more aligned with patients' needs and hopefully encourage more participation.

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Other groups are promoting technology to help overcome the challenges faced by some trial participants in getting to a distant research center, such as travel expenses, lost work time and arranging day care. Wearable biosensors and mobile apps could collect data from patients at home, supplemented with visits to their local physician.

“A lot of the bigger pharmaceutical companies have been testing this stuff for five years and are ready to start using the work they've done,” says Joe Dustin, the principal of mobile health at Medidata, a company that helps industry and academic researchers use technology in clinical trials. “There's a huge amount of untapped potential.”

Watchdog groups want the clinical trial process to be more transparent. Trial sponsors, from pharmaceutical companies to academic institutions, are supposed to register certain trials in a central government database and supply a basic summary of results within a year after the trial is completed. But not all comply. There is not much reward for doing so, and the FDA has imposed no penalties so far, say transparency advocates.

“If we want to have an unbiased understanding of the effects of medical interventions, we have to make sure that we're aware of all the evidence that's out there,” says Peter Doshi, an assistant professor of pharmaceutical health services research at the University of Maryland.

Greater transparency might encourage more physicians to refer patients to trials. Eighty-one percent of respondents in a 2017 national public opinion survey said they were “very” or “somewhat likely” to participate in a clinical trial if their doctor recommended one.6 But there are many reasons for doctors' reluctance.

“Clinical research is not taught or emphasized in medical education, so a lot of physicians are kind of agnostic about drug studies and are unaware of them,” says Sarah Ebner, president of Investigator Support Services, a Chicago firm that helps trial sponsors select research sites and investigators recruit and retain participants.

“There's also a financial disincentive,” says Ebner. Doctors are not reimbursed for the time it takes to find appropriate clinical trials for a patient, figure out whether the patient is eligible and discuss participation, she says. And studies indicate physicians may have a strong inclination toward existing treatments. Physicians and nurses refer fewer than 0.2 percent of the patients they see annually to clinical trials, according to the Tufts Center for the Study of Drug Development.7

Expanding minority participation is another stubborn problem, which can hinder the ability to generalize research findings to minority patients. One study found that black patients were underrepresented in government-sponsored trials to treat breast, lung, colorectal and prostate cancer, although another large study found no such problem. However, minority underrepresentation is clearly an issue, research shows, in trials that enroll healthy volunteers for prevention treatments.8

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For example, African-Americans account for more than one-fifth of all Alzheimer's cases in the United States but represent only 3 to 5 percent of participants in clinical trials of therapies for the disease.9

Lack of trust in the research process may contribute to low minority participation rates. While almost 40 percent of non-Hispanic white respondents to a 2017 national survey said lack of trust is one reason individuals do not participate in clinical trials, 50 percent of African-Americans and slightly more than 40 percent of Asians and Hispanics cited a lack of trust.10

Meanwhile, President Trump has called for speeding up the FDA approval process for new drugs, but experts say it is already the fastest in the world after decades of streamlining. In fact, some watchdogs say it is too speedy, sometimes allowing unsafe drugs on the market. After completion of Phase III of clinical trials, it takes an average of 10 months for a new drug to get approved once a company submits its application, according to the FDA.11

Trump is also poised to sign so-called Right to Try legislation passed by the Senate last year and the House in May. It would allow patients and their physicians to bypass clinical trials and request an experimental drug directly from a drugmaker without FDA approval. Right to Try laws have been adopted in 40 states and are pending in the other 10.

As the discussion about clinical trials continues, here are some of the questions researchers, patient advocates, physicians and regulators are asking:

Should clinical trials be made more transparent?

The U.S. Justice Department announced the largest health-care fraud settlement in U.S. history in July 2012, when the British pharmaceutical giant GlaxoSmithKline agreed to pay $3 billion to settle civil and criminal charges that it had misled the public about the efficacy and safety of several drugs, including the antidepressant Paxil.

In 1999, the FDA approved Paxil for adults, but the government said the company had used dinners, lunches and spa programs to influence doctors to promote the drug's use for children and adolescents. It also alleged that the company helped prepare a journal article that falsely claimed Paxil was effective in a clinical trial in patients under age 18. In addition, the government said, the company hid two other studies that failed to show the drug worked in youngsters.12

Over the past two decades, momentum has grown to make clinical trials more transparent, in large part because of such incidents. “If you don't have all the evidence in front of you and are just looking at a set of papers … that a sponsor would like you to see, you're likely to see a presentation that's skewed,” says the University of Maryland's Doshi, an associate editor at The BMJ, a peer-reviewed medical journal.

In 2007, Congress enacted the Food and Drug Administration Amendments Act (FDAAA), which required trial sponsors to register most post-Phase I clinical trials on ClinicalTrials.gov, a publicly accessible searchable database of federally and privately supported clinical trials. Trial sponsors also were required to provide a basic summary of results, both positive and negative, within a year after trial completion. In 2016, the U.S. Department of Health and Human Services (HHS) expanded and clarified those requirements.13

Separately, the National Institutes of Health (NIH), the primary government agency responsible for biomedical and public health research, issued a complementary policy requiring that all NIH-funded trials register and report summary results to the database. The NIH funds about one-fifth of all U.S. biomedical research. Industry funds most of the rest.

Christian Hinrichs, right, a researcher at the National Cancer Institute, shows cancer patient Fred Janick the difference between his scan showing cancerous tumors (right screen) and a clean scan (left screen) after treatment during a clinical trial. Last fall, the American Society of Clinical Oncology and the Friends of Cancer Research think tank called for increased patient access to clinical trials without sacrificing safety. (AFP/Getty Images/Saul Loeb)

While watchdog groups estimate that most applicable trials are being registered on the database, many sponsors are not reporting their summary results on time — or at all, they say.

“Everyone has been talking about this problem for far too long,” said Ben Goldacre, a senior clinical research fellow at the University of Oxford's Centre for Evidence-Based Medicine and one of the founders of FDAAA TrialsTracker, a website that monitors the ClinicalTrials.gov database daily for compliance. “We hope that increasing accountability will help to drive change forward.”14

In January 2018, the first trials covered by the updated regulations were due to report results. But as of mid-May, the results for about half of 595 trials had been reported late or were overdue, according to FDAAA TrialsTracker. Yet, so far the FDA has not assessed any fines against the drug companies, device makers, academic institutions or hospitals that have violated reporting requirements.15

Without fines, there is little incentive for reporting, and there are few carrots for compliance, says Doshi, except some good publicity from watchdog groups. In addition, academic study teams often disband once a trial is completed, and reporting results to ClinicalTrials.gov becomes an administrative burden with little reward, he says.

The Washington-based Pharmaceutical Research and Manufacturers of America (PhRMA), the main industry trade group, says on its website the industry remains committed to “sponsoring and conducting clinical research that fully complies with all legal and regulatory requirements.”16

Advocates for disclosure and transparency want the federal government to go even further: They want the FDA to release the detailed data that trial sponsors report to the agency when seeking approval for a medical intervention. These so-called clinical study reports are much more granular than the basic summary information submitted to ClinicalTrials.gov.

The reports contain information about enrollment, study methods, the primary and secondary endpoints, or intended outcomes, and how patients responded. The reports include tables and charts in appendices and can run to more than 1,000 pages.

In January, the FDA announced a pilot study, in which it will post redacted portions of clinical study reports for up to nine recently approved drugs. It asked companies to volunteer. The FDA will exclude confidential commercial information, trade secrets and personal patient information. So far, the agency has published information for the cancer drug Erleada from Janssen Biotech, a subsidiary of Johnson & Johnson, based in Horsham, Pa.17

But the United States lags behind European regulators, who began releasing complete clinical study reports in 2016. Tianjing Li, an epidemiologist at Johns Hopkins Bloomberg School of Public Health, would like to see the FDA release such reports for all approved drugs in the United States.18

Attorney Ann Witt, counselor to the FDA Associate Commissioner for Public Health Strategy and Analysis, defends the limited pilot program. “We haven't gone this path before, and we're really trying to find out if this is useful,” she says.

Besides, she says, U.S. law and regulations prevent the FDA from following in Europe's footsteps. “We can never release trade secrets,” she says. A trade secret can be a manufacturing method or process or something secret about the formulation of a drug.

“FDA officials are individually liable for releasing information that is protected by law,” says Witt.

For the FDA to be allowed to release complete clinical study reports, Witt says, “We would almost certainly have to change our regulations, and we might need new legislation from Congress.”

Should participation in clinical trials be less restrictive?

Eligibility criteria for determining who will be allowed to participate in a clinical trial are both inclusionary (specifying that participants must have a particular tumor type, for example) and exclusionary (barring patients with an unrelated heart condition, for example). They are designed to keep out patients who might suffer undue harm from the experimental therapy and to produce a homogeneous study group that will experience similar treatment effects.

The criteria are written by the trial sponsors or by the investigators who conduct the trial.

But many physicians believe the guidelines are out-of-date and overly narrow, keeping the nation's clinical trial participation rate too low. “It's been really just getting out of control,” says Edward Kim, an oncologist in Charlotte, N.C.

In fact, sometimes the criteria are so strict that the ideal participant does not exist and the trial cannot recruit any patients, says Pamela Tenaerts, executive director of the Clinical Trials Transformation Initiative, an organization in Durham, N.C., that works to improve the quality and efficiency of clinical trials. “They are looking for unicorns,” she says.

And if overly narrow eligibility requirements result in participants who do not resemble the kinds of patients doctors see in practice, they can lead to disappointing results once a drug is approved and physicians start prescribing it.

“We don't really know how tolerable or effective a drug in clinical trials will be in the patients we see day-to-day, [who] often have disease complications and other health problems,” said Rafat Abonour, a multiple myeloma specialist at Indiana University. “I am usually disappointed to find that drugs are less effective and have more side effects than reported in the studies.”19

In addition, even if a patient benefits from a newly approved medical intervention, insurance may refuse to pay for it because the patient does not resemble the participants in the study, says Kim. The problem could be something as simple as the patient being older than the cutoff age in a trial.

Part of the problem is habit, say experts. Too frequently, eligibility criteria are simply duplicated from trial to trial even if they are not necessary for a particular study, according to a 2017 paper in The New England Journal of Medicine. In addition, sponsors and investigators do not want to jeopardize trials with participants who are too sick.20

“There's a joke that you have to be able to run a marathon before you can participate in a clinical trial,” said Abonour.

As a result, HIV-infected patients commonly are refused entry to clinical trials, even if they are stable and healthy. Also routinely excluded are patients with a prior cancer, even if they were treated decades earlier and are unlikely to relapse. And patients whose cancer has spread to the brain are often denied access.21

“Nothing is more frustrating than when you have a patient with brain metastases, and you treat them with radiation and now they're stable, but they're still not included in a trial,” says Kim. “This has been slowly changing, but we need to accelerate this.”

Last fall, a joint task force of the American Society of Clinical Oncology (ASCO) a network of oncology professionals based in Alexandria, Va., and Friends of Cancer Research, a Washington-based think tank, issued a statement calling for changes designed to increase patient access to trials without sacrificing safety. Kim was the lead author.22

The task force proposed liberalizing the eligibility criteria for healthy, HIV-infected patients, those with stable brain metastases, teenagers who could benefit from being included in adult trials, patients with abnormal kidney function and patients with a history of cancer.

But making such changes will not be easy, said Mikkael Sekeres, director of the leukemia program at the Cleveland Clinic's Taussig Cancer Institute. Determining eligibility criteria is an “inherently complicated and high-stakes process.”23

In fact, the number of eligibility criteria has been multiplying in recent years, according to several analyses.24 The explosion in precision medicine, which allows physicians to tailor therapies to individual patients, has contributed to that increase. For example, an experimental drug might be known to work only in patients whose cancer cells have a particular genetic mutation.

Another factor may be that trial sponsors rely on what has worked in the past, says Doug Peddicord, executive director the Washington-based Association of Clinical Research Organizations, whose member companies conduct or help manage medical research for sponsors.

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“People are reluctant sometimes to do things differently than they have been done because the way they've been done has led to regulatory approvals by the FDA, for instance,” says Peddicord, who says the changes proposed by the task force “make great sense.”

But Kim says the FDA appears to approve of his proposed changes. A paper written by FDA scientists last year made the same recommendations.25

Is the FDA approving drugs too quickly?

The FDA has expedited the approval of drugs for serious or life-threatening diseases or conditions under its Accelerated Approval Program, created in 1992 during the height of the HIV/AIDS crisis. Currently, about 10 percent of new drugs, and about a quarter of new cancer drugs, are approved for market through the accelerated process.26

In the standard approval process, trials must show a clinical benefit, such as that a drug lengthens lifespan or reduces heart attacks or strokes.

But these outcomes can take years to measure. To save time, the Accelerated Approval Program allows trials to measure so-called surrogate endpoints, such as tumor shrinkage for cancer drugs.

These surrogate endpoints must be “reasonably likely to predict a [clinical] benefit but not a sure thing,” says Robert Temple, deputy director for clinical science at the FDA's Center for Drug Evaluation and Research.

And when the FDA grants accelerated approval to a drug, it requires the manufacturer to conduct followup studies once physicians start prescribing it. These studies are supposed to confirm a clinical benefit and reveal any harms that might not show up until later.

But the program has generated considerable controversy.

“The FDA may be approving many costly, toxic drugs that do not improve overall survival,” wrote oncologists Chul Kim, from NIH, and Vinay Prasad, from the Oregon Health and Sciences University.27

And some experts criticize how followup studies are done. “A lot of newer drugs approved through this pathway are not then being subjected to rigorous confirmatory trials in a timely fashion,” said Aaron Kesselheim, an associate professor at Harvard Medical School, who studies regulation and drug development.28

But others praise the program. “The FDA has a fine line to walk between accelerating access to drugs for patients who need them and demanding high-level evidence of safety and effectiveness,” says Richard L. Schilsky, the chief medical officer for ASCO. “The evidence shows that most of the time in oncology, they've been getting it right.”

“A good question is whether [drugs that have received] accelerated approval, which can make the drug approval fast because you have a much lower demand for data, have turned out to be terrible, not work or unsafe,” says Temple. “And we don't think that's been shown.”

Sometimes, the FDA allows drugmakers to use surrogate measures in the standard approval process as well, if the regulators have full confidence in the surrogates. For example, “We know enough from many studies that a drug that lowers your blood pressure in a sustained way will decrease the rate of stroke,” says Temple.

But some public health experts say many surrogate endpoints are not as reliable as the FDA says.

Joseph Ross, an associate professor of medicine and public health at the Yale School of Medicine, says, for instance, that while the amount of HIV virus in the blood is “extremely predictive of the clinical outcomes” for HIV patients, other surrogate measures used in trials of therapies for diabetes, cancer and cardiovascular disease are not nearly as good at predicting improved health or decreased mortality.

Problems also exist with post-market follow-up studies, say Ross and others.

“Those studies are sometimes not well designed or they are delayed. Sometimes they will take five or 10 years to complete,” says Michael Carome, director of the Health Research Group at Public Citizen, a consumer rights advocacy group in Washington. In the meantime, he says, “there could be injury to patients from the drug.”

Kesselheim and other researchers reviewed 22 drugs that were conditionally approved between 2009 and 2013 through the Accelerated Approval Program. The FDA required 38 confirmatory follow-up studies on these drugs once they were in the marketplace. But three years after the last drug's approval, only half of those studies had been completed. Of those, “most showed some benefit but relied on surrogate measures rather than clinical outcomes,” the reviewers said.29

Without timely and rigorous confirmatory studies, we think a drug works but we just don't really know, Ross says.

But Temple says there is no required time limit to complete follow-up studies. “We push as hard as we can,” he says. “[Trial sponsors and investigators] have to report to us each year on how they're doing, and we watch over it and we yell at them and raise our eyebrows.”

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Background

Early Clinical Trials

The Scottish surgeon James Lind is considered a pioneer in clinical trials. Serving as a surgeon in 1747 aboard the British Navy's HMS Salisbury, Lind was appalled by how many sailors were dying of scurvy, caused by a vitamin C deficiency. Their symptoms progressed from weakness and sore limbs to tooth loss, bleeding sores and infection.

At the time, the cause of the disease was unknown and there was no treatment, but Lind set out to find one. He selected 12 sick sailors, who “were as similar as I could have them,” he wrote in a 1753 paper. The 12 had the same symptoms, living conditions and diet, which reduced the likelihood that any differences among the sailors would skew the study's results.

Lind divided the men evenly into six groups, giving each group a unique treatment: vinegar; cider; sea water; oranges and lemons; diluted sulfuric acid; or a paste made from garlic, mustard seed, dried radish root and gum myrrh.30

“The most sudden and visible good effects were perceived from the use of oranges and lemons,” he wrote. However, Lind did not grasp the fruits' underlying benefit. He and his contemporaries “had no concept of vitamins — let alone vitamin C,” according to The James Lind Library, an online source devoted to Lind.31

In another early study demonstrating the importance of controlled comparisons, English physician John Snow compared neighborhoods served by different water sources and was able to trace an 1854 London cholera outbreak to one public water pump.

In 1881, French biologist Louis Pasteur demonstrated the efficacy of anthrax inoculation on two animal herds. And in 1901, U.S. Army physician Walter Reed conducted an experiment in Cuba, showing that yellow fever was transmitted by mosquitos rather than through infected persons.32

These important trials were for preventive measures; clinical trials of treatments were less common.

“The problem was not a lack of drugs for testing,” wrote historian Marcia L. Meldrum of UCLA. Manufacturers of prescription drugs and patent medicines — trademarked products often containing alcohol or opium derivatives and available over the counter — proliferated during the second half of the 19th century. And many made extravagant curative claims for their products, leading investigative journalist Samuel Hopkins Adams to label the drug industry “The Great American Fraud” in a series of articles in 1905.33

While individual physicians might be skeptical about the value of these preparations, they typically did not have the time, expertise or resources to test them.34 Even when comparison trials were possible, in hospitals or during epidemics, “there were often strongly urged ethical and professional injunctions against setting aside one group of patients for treatment which might be less effective than the accepted old or the promising new regimen,” wrote Meldrum.35

“What was lacking was a strong professional rationale justifying clinical comparative studies and an organizational infrastructure to support these studies on a large scale,” Meldrum said.36 Until 1901, the National Institutes of Health, founded in 1887, had only one full-time staff member. In 1901, Congress gave it funds to expand and to regulate the production of vaccines and antitoxins.37

The American Medical Association (AMA), an association of physicians and medical students, encouraged the federal government — unsuccessfully — to evaluate the quality and composition of all new drugs. So in 1905, the AMA established a Council on Pharmacy and Chemistry, which charged manufacturers a fee to analyze the quality of their drugs and certified those that passed muster.38

Council members began with a laboratory analysis, dismissing drugs whose principal ingredients were inert or whose active ingredients varied wildly from dose to dose. They next turned to animal studies to test therapeutic value. But the council recognized, at least theoretically, that the ultimate test would need to be on humans.39

However, council pharmacologists were overwhelmed by the volume of their laboratory work and “were in no position to produce their own clinical data,” wrote historian Harry M. Marks. But rather than commission trials, the council “relied on the opinions and recommendations of trusted colleagues,” wrote Marks. The AMA's drug certification program eventually ended in 1955.40

The 1906 Pure Food and Drug Act created a small agency — the forerunner of the FDA, which was established in 1930 — to seize adulterated or misbranded products involved in interstate commerce. But the agency was not authorized to screen drugs before they came to market or require manufacturers to conduct clinical trials.41

Gold Standard Emerges

Still, researchers, primarily infectious disease experts, were conducting clinical trials around the world, and during the first several decades of the 20th century a growing number of researchers adopted a method called alternate allocation to reduce bias and chance.

Under this system, patients enrolled in a study were alternately assigned to one treatment or another. Or patients enrolled on alternative days got different treatments. One group might be a “control,” receiving either a dummy treatment, known as a placebo, or the standard therapy of the day. Researchers would then compare the outcomes of the two groups.

Many of these trials tested interventions to prevent or treat public health threats such as dysentery, cholera, diphtheria, gonorrhea, influenza, malaria, pneumonia, scarlet fever, and tuberculosis. The experimental interventions included antibiotics, antiseptics, diet, gamma globulin, amino acids, vaccines, vitamins and other approaches.42

But alternate allocation had a major weakness. The people responsible for recruiting trial participants knew the allocation schedule in advance and could cheat. For example, if patients enrolled on a Monday were assigned to the experimental drug and those enrolled on a Tuesday were assigned to a placebo, recruiters could game enrollment by giving the healthiest patients the experimental drug in order to get better study results.

In the meantime, one of the deadliest mass poisonings of the 20th century in the United States called attention to the limitations of drug regulation. In 1937, the S. E. Massengill Co. liquefied the antibacterial agent sulfanilamide, used to fight strep throat, by dissolving it in a toxic solvent. However, Elixir Sulfanilamide was marketed without ever being tested in animals or humans, since no law required such testing. More than 100 patients died.43

FDA agents seized every bottle they could find. “The FDA, however, was only empowered to act against the deadly product because it was misbranded,” wrote historian Suzanne White Junod. An “elixir” must contain alcohol, which Elixir Sulfanilamide did not.44

Following the disaster, Congress passed the 1938 Federal Food, Drug and Cosmetic Act, which authorized the FDA “to act before, not after, the hazards of a drug were revealed through distribution on the open market,” wrote Marks. The FDA considered a drug to be “safe” if its therapeutic benefits outweighed any harms to patients.45

Under the law, pharmaceutical companies had to provide information on any and all clinical investigations to the FDA, which could include expert testimonials, patient case studies and clinical trials; a list of the drug's components; a description of manufacturing methods; and copies of the drug's packaging and labeling. And for the first time, the FDA could inspect factories.46

The agency conducted laboratory analysis to screen most new drugs and rejected those that were toxic or whose main ingredients were inert. Manufacturers were not required to conduct animal studies, although the FDA could request them. The agency chose not to test the limits of its new authority by requiring controlled clinical trials or regulating their methodology.47

Nevertheless, methodologies were improving as academic, government and industry researchers became more experienced. Then after World War II, British researchers at the Medical Research Council, a government-chartered agency that funds and coordinates medical research, conducted a groundbreaking study that led to the eventual widespread acceptance of the randomized controlled trial, or RCT, as the gold standard in research.

Concerned about the shortcomings of alternate allocation, British epidemiologist and biostatistician Austin Bradford Hill took a different approach in his 1947 trial of streptomycin and tuberculosis. Hill and colleagues used a system of random number assignments, much like a coin toss, to allocate 107 patients to the experimental group, which received the antibiotic and bedrest, or to the control group receiving just bedrest. Randomization prevented researchers from interfering in the assignment process.

And, while the investigators and patients knew who was receiving the drug, the radiologists interpreting the patients' subsequent X-rays did not. They were “blinded” to eliminate the impact of any unconscious bias. The study showed that streptomycin cured tuberculosis, and the results were soon replicated in a randomized controlled trial sponsored by the U.S. Public Health Service.48

“The question remained whether [RCTs] would gain acceptance outside the small circle of physicians who acted as government advisors,” wrote Meldrum.49

In 1954, the trial of virologist Jonas Salk's experimental polio vaccine helped to favorably sway medical opinion. The National Foundation for Infantile Paralysis, a volunteer organization that raised funds for polio research, sponsored a strictly randomized, placebo-controlled trial in children ages 6–9 in 11 states. The trial was “double-blind.” In other words, neither the researchers nor the patients knew who got the vaccine and who received the placebo. In that way, they would not be biased when looking for polio symptoms. In the study, the vaccine was 80–90 percent effective in preventing polio.50

In the 1950s and '60s, researchers began evaluating whole new classes of drugs to treat chronic diseases such as high blood pressure, heart disease and cancer.51 Nevertheless, pharmaceutical companies were often reluctant to put the time and money into randomized controlled trials, because the government did not require them, according to The New England Journal of Medicine. 52 That did not stop companies from defending high drug prices during congressional hearings in the late 1950s by pointing to their investment in research.53

But expert testimony at the hearings pointed to the shoddy state of industry research, according to an FDA history of clinical trials. For example, Louis Lasagna, an expert in clinical pharmacology, testified that adequately controlled comparisons of drugs were “almost impossible to find.”54

It took another drug disaster to bring the randomized controlled clinical trial into mainstream research practice.

In 1961, thalidomide was discovered to have caused significant birth defects and stillbirths in babies whose mothers had taken the drug early in pregnancy to quell morning sickness. One year later, Congress enacted the Kefauver-Harris Amendments to the 1938 Food, Drug, and Cosmetic Act.

The amendments required that new drugs be proved efficacious in “adequate and well-controlled investigations.” The law did not define those terms, but by the end of the decade, the FDA was requiring randomized controlled trials for the approval of all new drugs.55

Protecting Human Subjects

In 1972, Peter Buxtun, an employee of the U.S. Public Health Service, leaked information to reporters about the agency's 40-year-long Tuskegee Syphilis Experiment. Its researchers had been studying syphilis in hundreds of impoverished African-American men in Alabama without their informed consent and had denied them penicillin, known to be an effective treatment since the 1940s.56

The scandal ended the study and spurred passage of the 1974 National Research Act, which created an ethics commission to identify basic principles of research conduct and suggest how to ensure those principles were followed.57

New regulations created under the law also required researchers to get voluntary informed consent from all persons participating in studies done or funded by the government. Institutional review boards were set up to review study protocols to make sure they met ethical standards.58 A protocol is a written document detailing the trial's objectives, design, methodology, organization and safety measures.

These boards, housed at universities and other organizations that accept federal funds for human research, are composed of at least five members from scientific and nonscientific backgrounds. They can deny, accept or request modifications to a study.59

In the 1980s and '90s, the Department of Health and Human Services (HHS) and Congress strengthened protections for patients participating in clinical trials. For example, the 1996 Health Insurance Portability and Accountability Act (HIPAA) required researchers to tell patients how their health information is stored and kept private.

By this time, industry had become the primary sponsor of clinical trials, far surpassing the NIH and academic institutions, a trend that continues today. A 2015 study by Johns Hopkins University found that the drug and medical device industry funds six times more clinical trials than the federal government.60

But companies have a conflict of interest, because they make money if their trials succeed and the FDA approves their products. Such conflicts can “have a pervasive influence on the research questions that are asked, the ways that studies are designed, the framing of the analyses and results, and the decision to disseminate the findings,” said radiologist Reshma Jagsi, director of the University of Michigan's Center for Bioethics and Social Sciences in Medicine.61

In addition, the drug and medical device industries and academic researchers have a history of not reporting the results of negative clinical trials.62 In response, Congress passed the Food and Drug Administration Modernization Act of 1997, which required the NIH to create a public registry for certain clinical trials regulated by the FDA. The website, ClinicalTrials.gov, went live in 2000.

In 2007, Congress expanded the kinds of trials that must be registered and required researchers to submit more information about them, including summary results, whether positive or negative, once a trial ends. In 2016, the HHS mandated that researchers submit results even for products that never receive FDA approval.63

In response to a huge lobbying effort from the pharmaceutical industry, in December 2016 Congress passed, with bipartisan support, the 21st Century Cures Act. While supporters said the law was needed to streamline and speed up drug approval, many physicians and bioethicists cautioned that its provisions could hurt the public's trust in the FDA by reducing its reliance on randomized clinical trials.

Among other things, the law mandated that the FDA evaluate whether “real world evidence” should be used in follow-up studies that sometimes are required for approved drugs and when considering new uses for existing drugs. That evidence can come from ongoing safety surveillance, observational studies, patient registries and insurance claims; in other words, not from randomized controlled trials.64

“These provisions would unravel the FDA, turning it from the treatment watchdog it is today into a puppet of the pharmaceutical and medical device industry,” wrote Baltimore physicians Reshma Ramachandran and Zackary Berger a few weeks before President Barack Obama signed the act into law in late 2016.65

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Current Situation

Funding for Clinical Trials

President Trump wants to cut the budget of the National Institutes of Health, the world's largest single funder of basic biomedical research, the kind of research that may not have immediate commercial applications but that lays the essential groundwork for medical advances.

In February, the White House proposed an NIH budget for fiscal 2019 of $34.8 billion, a 6 percent reduction from the $37 billion Congress appropriated for fiscal 2018.66

Industry is by far the biggest funder of all U.S. medical and health research, spending an estimated $116 billion in 2016, more than twice as much as all other sources combined, including the federal government, academic and research institutions, foundations and state and local governments.67

But the federal government, mostly through the NIH, plays an important role, funding an estimated 22 percent of overall research in 2016, according to Research!America, an alliance of companies, hospitals, universities, foundations and professional societies advocating for greater funding of health and medical research.68

A nurse takes the temperature of a volunteer in a clinical trial of a vaccine for the deadly Ebola virus at Redemption Hospital in Monrovia, Liberia. The study, expected to include 27,000 people, is being conducted by the U.S. National Institutes of Health and the Liberian Ministry of Health. (Getty Images/John Moore)

Yet, between 2005 and 2015, the number of NIH-funded clinical trials registered in the ClinicalTrials.gov database annually fell from 1,580 to 930 — a drop of more than 40 percent, according to a recent analysis.69

“One would have hoped that this decline in numbers was compensated by a rise in larger-scale, higher-quality trials, but that wasn't so,” said senior author Curtis Meinert, an epidemiology professor at the Johns Hopkins Bloomberg School of Public Health. Over the same period, only 10 percent of trials enrolled more than 500 participants. The median number of participants in NIH-funded clinical trials totaled 64, corresponding to 32 people in a treatment group and 32 in a control group.70

“The sample size is a serious issue,” said Meinert. “The NIH trial sizes in general seem to have been too small — many would have been unlikely to detect meaningful differences in outcomes.”71

Meinert and his co-authors concluded that the annual drop in the number of NIH-funded trials was due in part to the decline in the NIH budget over the decade, which was down about 20 percent after adjusting for inflation.72

The funding situation has improved since then. Although Congress' appropriation for fiscal 2018 more than compensated for inflation since 2015, it is unknown what Congress will do about President Trump's request to cut the fiscal 2019 budget.73

Complexity Increases

All phases of clinical trials have become much more complex since 2005, leading to rising costs, longer trial duration and added difficulties in recruiting and retaining participants, according to the Tufts Center for the Study of Drug Development, a research center at Tufts University.74

Kenneth Getz, director of sponsored research programs at the center, says complexity has increased by almost every measure. Among the variables that have increased in trials since 2005 are the total numbers of investigative sites that participated in trials, exclusion and inclusion criteria for participants, unique procedures performed and their frequency, according to the center's analysis.

Multiple factors contribute to this trend, says Getz. “We've seen a shift away from [studying] acute illnesses to chronic diseases that require more measurements or much longer observation periods and more procedures,” he says. Trials might be gathering data on a diagnostic tool that is paired with an experimental therapy or they might be examining a combination treatment with multiple therapies, he adds.

Meanwhile, companies are trying to make every research dollar go further, so they are gathering data pertinent to the drug being studied and other data that might help with future research, Getz says.

Paradoxically, he says, while trying to conserve money, companies are wasting it, because much of the added complexity is unnecessary, says Getz. But it is difficult for companies to change, he says. The risk involved in developing a new drug, one that may significantly impact a company's future, makes it difficult for research scientists and senior managers to make that tough decision to simplify a trial protocol, he says.

Getz speaks frequently with companies about the complexity problem, and many have begun to streamline trials, he says.

“I'm fighting the big fight,” he says. “It takes a lot of work to move and modify a really entrenched behavior or practice.”

Umbrellas and Baskets

Scientists now know that cancers are driven by genetic changes and that patients may benefit if their treatments are tailored precisely to the particular genetic mutations, or markers, in their cancer cells — a process called precision medicine.

“While the rise of precision medicine has improved many aspects of patient care, it has also exacerbated the challenges of running a clinical trial,” according to the website for Lung-MAP, a lung cancer clinical trial. The need for “smaller, targeted patient populations” makes it more difficult to recruit eligible patients.75

So in recent years, researchers have devised ways to make the recruitment process easier for clinical trials of precision drugs. Two of the approaches are called “umbrella” and “basket” trials.

Typically, in precision medicine trials, a cancer patient would find a clinical trial for her cancer, get her cancer cells genetically tested and then wait to find out whether she is eligible for that trial. If not, she would go on to the next trial and the next, hoping to find a match between her cancer's genetic profile and an experimental therapy. It is a time consuming and sometimes demoralizing process.

In contrast, patients enrolled in an umbrella trial are tested just once and then assigned to one of many sub-studies, or arms of the trial, each testing a different drug targeted to a different genetic mutation. It involves the cooperation of multiple drugmakers and research groups operating under one master protocol.

Lung-MAP is a groundbreaking umbrella trial, begun in 2016, which involves collaboration among the National Cancer Institute, several pharmaceutical companies, several lung cancer advocacy groups and other organizations. It is testing five different experimental therapies at hundreds of large and small medical centers across the country.

It is open to patients with advanced-stage squamous cell lung cancer whose disease has not responded to standard therapy. No one in the study will receive a placebo. If a patient's cancer does not have one of the necessary genetic changes, the patient may be placed in an arm of the study that is testing immunotherapy drugs — medicines that activate the patient's immune system to fight cancer cells.

While promising, umbrella trials “are not easy — their modular structure is quite complex and can lead to various arms being moved in and out of the study as new drugs become available and results from testing of other drugs become clear,” said George Weiner, director of the University of Iowa Holden Comprehensive Cancer Center.76

A basket trial is different. It tests one experimental therapy against one genetic marker. Patients with the genetic abnormality can enroll regardless of where their cancer originated — in the lung, breast, kidney or any other organ.

As they become more widely available, “umbrella and basket trials for molecular targets offer several major benefits for developing new treatment approaches,” said physician Howard West, an editor at the journal JAMA Oncology. “It is possible to identify options for small subgroups, perhaps even with a marker seen in only 1 percent or 2 percent of a broad cancer patient population.” Moreover, patients may not have to travel far to participate because more hospitals and medical practices participate, and new treatments can be tested for commercial use faster, said West.77

Right to Try

Advocates for the terminally ill who have been fighting for a Right to Try law have reason to celebrate. The House passed a Right to Try bill in May, the same bill the Senate passed last year. President Trump, a vocal supporter, is expected to sign it into law.

The law would allow physicians to request experimental drugs directly from manufacturers without FDA permission. The drugs would have had to complete only a Phase I trial, which tests safety but not the efficacy of the drug.

This spring, the libertarian advocacy group Americans for Prosperity, based in Arlington, Va., and funded by billionaire brothers David H. Koch and Charles G. Koch, launched a digital and television advertising campaign promoting the Right to Try agenda.78

Opponents of Right to Try, including regulators, drug companies and some patient advocates, point out that the FDA already provides access to experimental medications for the terminally ill through its Expanded Access Program. The program allows a physician to ask a pharmaceutical company for an experimental drug for a terminally ill patient. If the company agrees to supply it, the doctor then asks permission from the FDA to proceed.

The FDA has said that it authorizes more than 99 percent of such requests, and that emergency requests are granted over the phone and all others are processed in about four days.79

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Outlook

More Transparency?

Doshi of the University of Maryland says much more progress is needed in persuading trial sponsors and the FDA to routinely share detailed data from clinical trials.

Some people “feel that a lot has already been accomplished and we are where we need to be,” says Doshi. “I don't think that's the case.”

But he says he is optimistic that within 10 years trial transparency will have broader support.

Getz of the Tufts Center for the Study of Drug Development is optimistic that trial sponsors will figure out how to simplify clinical trials. “It's just not sustainable if we continue to see reductions in our success rates, if we continue to see a growing challenge in recruiting and sustaining study volunteers,” he says.

One promising approach, Getz says, is to tap into patients' knowledge and opinions when designing trials, and he expects more trial sponsors to do that.

“Patients can look at a study and say, ‘There is no way I'm going to spend seven hours at the investigative site during visit number three; I have to work, and I just can't do that.’ So getting that kind of feedback … from the patient community is really key,” says Getz.

However, patient eligibility criteria may buck that trend, says Peddicord of the Association of Clinical Research Organizations, by becoming increasingly restricted as a growing number of experimental drugs target precise populations with specific biomarkers.

Luckily, he says, the search to find those often relatively small, specific patient populations will become easier with the help of patients' electronic health records and other repositories of patient data. Recruiters will be able to better identify potential participants and “take a less scattershot approach,” he says.

Kim, the head of the joint task force of the American Society of Clinical Oncology and Friends of Cancer Research, agrees that the growth in precision medicine will narrow eligibility criteria to patients with particular genetic mutations, but it will also allow other eligibility criteria to be broadened.

“You don't need to exclude older people, very young people, people with some slight kidney dysfunction because these therapies are clearly targeted,” says Kim. “My gosh, you could put anybody in those studies and show a benefit because when you give the right drug to the right person who has the right signal in their tumor, these tumors melt away and people live longer.”

Ross of the Yale School of Medicine sounds a more pessimistic note. He expects the clamor for speedier drug approvals to continue over the next several years.

Congress, patients and doctors want drugs to be approved faster, he points out. “So there's a long line of people who are clamoring for earlier access,” he says, “and I may be one of the sole voices of hesitancy and caution saying ‘Hold on now.’”

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Pro/Con

Should terminally ill patients have the right to try experimental drugs outside of a clinical trial without FDA approval?

Pro Starlee Coleman Senior Policy Adviser, Goldwater Institute. Written for CQ Researcher, May 2018 Right to Try is a bipartisan movement to speed access to promising investigational drugs to terminally ill patients. Right to Try laws have been adopted in 40 states and introduced in the other 10. Similar legislation passed the Senate by unanimous consent in 2017 and the House in May. President Trump is expected to sign it into law. Some frequently asked questions: Is Right to Try safe? Treatments are limited to therapies that have successfully completed a Phase I safety trial and are in active Phase II or III trials or under final evaluation. Right to Try patients are at no greater risk than patients enrolled in the trials. Will sick people be preyed upon? Federal law blocks companies from marketing and profiting off unapproved drugs. Companies will not market investigational treatments to dying patients only to charge hefty fees. Will this hurt the clinical trial or Food and Drug Administration (FDA) drug approval process? No. Right to Try applies only to patients who cannot participate in a trial. And it relies on the FDA process to determine which treatments are available. If a treatment is no longer in an active trial, it is no longer available under Right to Try. Is this just false hope? No one makes that claim about clinical trials — even when some patients receive a placebo. These are the same treatments used in clinical trials. Besides, dozens of patients are alive because of Right to Try. The most important thing to remember is that Right to Try is completely voluntary. No patient is required to seek treatment, no doctor is required to provide treatment and no company is forced to make a treatment available that it believes will not benefit a patient. Further, a patient who wants the FDA involved can still apply through the agency's Expanded Access program. Right to Try does not replace that program, it is simply another pathway to treatment. Ultimately, a patient's risk tolerance is not something the government should determine. When patients seek investigational treatment after they have been fully informed of the risks — and after doctors and the manufacturer have decided the treatment could help — the federal government should not have a veto stamp.

Con Lisa Fullam Professor of Moral Theology, Jesuit School of Theology, Santa Clara University. Written for CQ Researcher, May 2018 Right to Try is wrong for patients. It would not give patients new rights and would undo important patient protections. Under Right to Try, terminally ill patients could ask drugmakers to let them use drugs that have passed Phase I testing — checked for safety but not effectiveness — and do so without FDA permission. Contrary to the Right to Try advocates' claims, most such drugs are not helpful in treating disease. Consider Jane, a hypothetical cancer patient who is not eligible for a research trial of a new drug. Under the current FDA Expanded Access Program, Jane's physician submits a request to the manufacturer and the FDA to allow Jane to try the new medication. The FDA's turnaround time can be as short as a phone call. Then, the Institutional Review Board at the relevant hospital (which includes physicians, nonscientists, such as ethicists, and community members) makes sure Jane is informed about known or expected side effects, results of prior studies, what her use of the drug would mean in terms of hospital time, tests, etc. The board reviews the process annually, noting any problems that have arisen. Adverse events, such as severe new side effects, also are reported to the FDA and may be taken into account if or when the drugmaker applies for the drug to be approved for sale. Under Right to Try, Jane and her physician are on their own with the drug company. Nothing in Right to Try requires that drug companies provide Jane with the drug — and they can pass on to Jane what can be crushing costs for the drugs or for their administration. Right to Try largely forbids consideration of the drug's adverse effects or lack of efficacy (if either is the case,) when deciding whether the drug should be approved for wider use. Under Right to Try, informed consent exists only between Jane and her physician, without further oversight. The drug company and the physician are largely immune from prosecution if something goes badly wrong. Right to Try leaves patients at the imperfect mercy of big drug companies if they are hurt by an ineffective or harmful new drug. Right to Try turns sick people into guinea pigs. Careful, scientifically sound and adequately overseen clinical research is the best way to protect patients and provide new, effective drugs.

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Short Features

Researchers Seek Patient Help in Designing Trials

Clinical trials of diabetes treatments focus almost exclusively on reducing the average measure of a person's blood sugar over three months. However, that measure — known as A1c — does not capture the sudden fluctuations in blood sugar that greatly concern diabetes patients.

Patients and advocacy groups urged the medical community to develop better ways to control the extreme highs and low in blood glucose.

A committee of leading clinical and research organizations listened, and last November it formally recognized the importance of developing such therapies.1

The patients' involvement was part of a larger trend in the world of clinical trials and medical research. Partly to make it easier to recruit trial participants, a growing number of pharmaceutical companies and research institutions have begun to court patients by asking for their suggestions in designing and planning the trials.

“We are talking about having patients sit at the table as equal partners next to the people who design clinical trials,” says Pamela Tenaerts, executive director of the Clinical Trials Transformation Initiative (CTTI), an organization in Durham, N.C., that works to improve the quality and efficiency of clinical trials. “The concrete benefit would be clinical trials that are more meaningful to people with the disease.”

However, “patient engagement” in trial planning is only slowly catching on. Among the challenges is getting companies to invest in the process.

“While patient engagement has been a hot topic across the industry for some time, actual investment in patient engagement was found to be weak,” said Anne-Marie Hess, an adviser at SCORR Marketing, a consulting company in Omaha, Neb., for the health care and pharmaceutical industries. In a survey the company conducted last year of trial sponsors and research organizations, 41 percent of respondents did not solicit any feedback from patients. Of those that did, most simply used surveys rather than reaching out to patients and advocacy groups for in-depth discussions. 2

Tenaerts says patients are more likely to enroll in trials they helped design than those they did not. And when consulted early, patients can weigh in on everything from trial objectives to logistics, says Tanisha Carino, executive director of FasterCures, which works to speed up medical research and is part of the Milken Institute, a think tank in Santa Monica, Calif., that studies links between the economy and social problems.

“Companies have found it very useful to share protocols with patients and ask, ‘Is it a reasonable expectation to have you come back to the [research] institution two or three times a week as part of the study?’” Carino says. Protocols describe a trial's objectives, design, methodology, organization and safety measures.

Although patient advocates have long helped researchers publicize clinical trials, advocates for people with HIV/AIDS in the 1990s were among the first to push for more patient input in the drug development and approval process. “But after that, almost nothing else happened in other disease groups,” Carino says.

Then in 2012, Congress' renewal of the Prescription Drug User Fee Act called for more patient perspectives in the drug-review process. The next year, the U.S. Food and Drug Administration (FDA) began holding 24 disease-specific listening sessions with patients and patient representatives to get their views on their conditions and available therapies. The first meeting was focused on chronic fatigue syndrome and the last, in May 2017, on autism. 3

Patient-focused drug development, as the process is called, is not without controversy.

The Parent Project Muscular Dystrophy (PPMD) advocates for patients with Duchenne muscular dystrophy, a rare disease that causes muscles in children, mostly boys, to quickly weaken and can result in death in early adulthood. PPMD, based in Hackensack, N.J., was among the first patient organizations to conduct a patient preference study. It found that patients and caregivers valued maintaining upper body strength and limiting the progression of the disease far more than improvement in the so-called six-minute walk test, the standard by which Duchenne therapies are tested. 4

In 2016, drugmaker Sarepta applied to the FDA for approval of Exondys-51, a drug to treat Duchenne that it had tested in a small trial. Participants who believed the drug slowed the disease's progression rallied to the cause. They persuaded the agency to approve Exondys-51 for patients with a particular genetic mutation, even though an FDA advisory committee had voted against approval because scores in the six-minute walk test had not improved. 5

The decision generated enormous debate among FDA staff, physicians, patients and insurance companies about the rightful influence of patients. Insurance companies initially refused to cover the medication.

“We want to ensure patients are protected, which means we must have a thorough review of robust scientific evidence before a new therapy is approved,” says Cathryn Donaldson, spokesperson for America's Health Insurance Plans (AHIP), a Washington trade group for insurance companies.

There are significant challenges to increased patient engagement, Tenaerts says. Companies and research institutions must budget for patient participation and find the right patients and advocacy organizations to approach, she says. Some patient groups may be effective at organizing a local 5K run to raise money and awareness of a disease, but they might lack expertise in medical research, she says.

And then there is the issue of time. “Your design phase of the trial may be lengthened because now you have to have discussions with patients about things that you didn't even know were an issue,” says Tenaerts.

— Barbara Mantel

[1] “Leading Diabetes Organizations Issue Consensus Statement Defining Health Outcomes beyond HbA1c,” JDRF, Nov. 21, 2017, https://tinyurl.com/y92etyue.

[2] Anne-Marie Hess, “Survey: patient engagement a low priority in clinical trials,” SCORR, April 9, 2018, https://tinyurl.com/yatkp7og.

[3] “The Voice of the Patient: A Series of Reports from FDA's Patient-Focused Drug Development Initiative,” Food and Drug Administration, https://tinyurl.com/y9vezrp7.

[4] “From Aspiration to Application: 5 Years of Patient-Centricity,” FasterCures, June 2017, https://tinyurl.com/yda8zp7z.

[5] Ibid.

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Could Digital Technology Transform Clinical Trials?

Drug developers are trying to figure out how to harness the explosion in smartwatches and other wearable biosensors, be it consumer devices such as the Fitbit or wearable technology developed just for trials, such as a body patch embedded with sensors.

It is the latest stage in the evolving use of digital technology in clinical trials. For more than a decade, trial participants have been using electronic devices, such as smartphones loaded with special apps, to keep a daily diary about pain, fatigue and other quality-of-life measures.

About a fifth to a quarter of clinical trials include such electronic patient reports, and many more could do so, says Joe Dustin, principal for mobile health at Medidata Solutions, a technology company that helps manage digital data for clinical trials.

But the adoption of wearable devices could transform clinical trials in much more significant ways than a smartphone app alone, say Dustin and others in the field.

Wearable devices are designed to capture a steady stream of data about vital signs, movement, breathing, sleeping and more that could be turned into objective, digital biomarkers against which the effectiveness of an experimental drug could be measured. For example, a sensor measuring tremors could help researchers figure out whether a drug for Parkinson's disease is working.

Pharmaceutical companies are testing the feasibility of using smartwatch sensors and other wearable biosensors in clinical trials to monitor participants' health and assess whether an experimental drug or treatment is effective. (Getty Images/Lisa Werner)

Traditionally, doctors have used subjective measures to assess a Parkinson's patient's progress in a trial, says Lauren Bataille, senior associate director of research partnerships at the New York-based Michael J. Fox Foundation, which funds Parkinson's research.

“A movement disorder specialist or a neurologist will ask the patient to do a series of movements, such as put their fingers together, walk a straight line, and then using their naked eye, they will assess the person's level of symptom severity and rate it on a scale of one to five,” she says. “We see using technology as an opportunity to create more objective measures.”

Incorporating wearables and biosensors into clinical trials enables investigators to receive a continuous stream of data rather than just a snapshot from an office visit, says Bataille. Using such devices could also enable patients who live far from a clinical trial site to participate.

But patients will still need to speak with physician researchers or at least continue to use a diary app, says Craig Lipset, head of clinical innovation at Pfizer, a pharmaceutical conglomerate in New York. “If you suddenly see less activity on an osteoarthritis patient's wearable that's on her wrist, is it because she's having pain and therefore isn't active?” asks Lipset. “Or is that patient now knitting, which she hasn't been able to do in years?” Patients will still need to fill in the context, he says.

The use of smartwatches and biosensors is in the very early stages. Drug companies have been testing their feasibility in observational trials and in early-phase drug trials, says Dustin, and have not yet begun to use them as true biomarkers in Phase III drug trials — large studies that test the efficacy of therapies.

For example, the Michael J. Fox Foundation helped to fund an observational trial with 953 participants in North America and the Netherlands. Patients wore a smartwatch, whose sensors collected data throughout the day and used an app on their smartphones to report their symptoms. Only a small number of people dropped out, and the majority provided data. Patients rated the usability of the system 62.5 on a scale of 0 to 100, somewhere between “OK” and “good.” 6

The foundation is now partnering with a technology firm to improve the software that interprets the data that wearables and sensors provide. The goal is to develop reliable, objective digital biomarkers that can be used in Phase III trials.

As of now, “there are no FDA-approved objective measures ready for prime time,” says Bataille. To speed up their development, the foundation is coordinating a consortium of 15 pharmaceutical and technology companies, called Digital Health Partners, to share information and lessons learned.

But other challenges remain, say experts, such as making sure the devices are reliable, the data are uniform across different brands, patients' privacy is guaranteed and patients don't view using the technology as just another burden of participating in a trial.

“Does that wearable have to be charged every night? Does somebody have to sync it up with some other device to get the data off? Is proper technical support being provided to the patient?” asks Lipset.

“I think this type of learning really only comes through working together with patients and getting their hands-on experience early,” he says.

— Barbara Mantel

[6] Ana Lígia Silva de Lima, “Feasibility of large-scale deployment of multiple wearable sensors in Parkinson's disease,” PLOS/One, Dec. 20, 2017, pp. 1, 5–11, https://tinyurl.com/y8mvgu8g.

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Bibliography

Books

Davies, Madhu, and Faiz Kerimani, eds., A Quick Guide to Clinical Trials , Bioplan Inc., 2008. Researchers describe the basics of clinical trials.

Dizon, Don S., ed., American Society of Clinical Oncology Educational Book , ASCO, 2017. Leading oncologists describe key developments in the field and highlight compelling research being conducted through clinical trials.

Marks, Harry M. , The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900–1990 , Cambridge University Press, 1997. A historian traces the process of experimentation and reform in U.S. medicine

Articles

Cohn, Meredith , “Industry funds six times more clinical trials than feds, research shows,” The Baltimore Sun, Dec. 15, 2015, https://tinyurl.com/hnmr7zj. The pharmaceutical and medical device industries are the top funders of U.S. biomedical research.

Li, Tianjing , “What's not shared — building on the FDA's transparency momentum,” The BMJ Opinion, Jan. 31, 2018, https://tinyurl.com/yaj3od6o. In a commentary, an associate professor at the Johns Hopkins Center for Clinical Trials and Evidence Synthesis in Baltimore argues that the U.S. Food and Drug Administration (FDA) should publicly release the detailed clinical trial data that companies submit to the agency.

Malakoff, David , “First take: Trump's 2019 budget not as disastrous for science as it first appears,” Science, Feb. 12, 2018, https://tinyurl.com/y78ygfc8. The administration's proposed fiscal 2019 budget for the National Institutes of Health would not cut funding as much as feared.

Silvestrini, Elaine , “Studies: Major Flaws Found in Some Drug Approvals,” Drugwatch, April 17, 2018, https://tinyurl.com/y9o9vf29. The FDA's Accelerated Approval Program for potentially lifesaving drugs includes too many non-randomized trials, say critics.

Swartz, Aimee , “Cancer clinical trials exclude many desperate patients. Should that change?” The Washington Post, Dec. 17, 2017, https://tinyurl.com/y8zrjhtd. Eligibility requirements are necessary to keep participants in clinical trials safe, but some physicians argue that the criteria are too strict and eliminate too many patients from trials.

Thompson, Dennis , “Is FDA Taking Close Enough Look at Fast-Tracked Drugs?” HealthDay, Aug. 15, 2017, https://tinyurl.com/y9k7taea. Critics say too many drug companies are late in completing required follow-up studies of drugs approved through the FDA's Accelerated Approval Program.

Reports and Studies

“Public Perception of Clinical Trials,” Research!America, July 2017, https://tinyurl.com/y9tkbmau. Americans are split on the importance of participating in clinical trials, according to a poll from a group promoting the importance of medical research.

“U.S. Investments in Medical and Health Research and Development 2013–2016,” Research!America, Fall 2017, https://tinyurl.com/yc398t33. Industry is the biggest funder of U.S. biomedical research, followed by the National Institutes of Health.

Junod, Suzanne White , “FDA and Clinical Drug Trials: A Short History,” U.S. Food and Drug Administration, Feb. 1, 2018, https://tinyurl.com/yazxry74. An FDA historian traces the history of clinical trials and relevant federal legislation.

Kim, Chul, and Vinay Prasad , “Cancer Drugs Approved on the Basis of a Surrogate End Point and Subsequent Overall Survival: An Analysis of 5 Years of US Food and Drug Administration Approvals,” JAMA Internal Medicine, December 2015, https://tinyurl.com/y8dr87co. Two oncologists question the safety and efficacy of recently approved cancer drugs.

Kim, Edward S., et al., “Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement,” Journal of Clinical Oncology, Oct. 2, 2017, https://tinyurl.com/y8o2x9ea. A joint task force representing two cancer organizations suggests ways to increase the participation rate for clinical trials.

Lígia Silva de Lima, Ana , “Feasibility of large-scale deployment of multiple wearable sensors in Parkinson's disease,” PLOS/One, Dec. 20, 2017, pp. 1, 5–11, https://tinyurl.com/y8mvgu8g. Parkinson's patients in a study successfully transmitted data from smartwatches, paving the way for use of the devices in clinical trials.

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The Next Step

Expanding Eligibility

Gerber, David , “Unnecessary exclusions shut patients out of clinical trials,” Stat, April 5, 2018, https://tinyurl.com/y8qyffu4. The inclusion of irrelevant rules when designing clinical trials leads to the exclusion of many patients, says the associate director for clinical research at a cancer center.

Ledford, Heidi , “Cancer researchers push to relax rules for clinical trials,” Nature, April 4, 2018, https://tinyurl.com/yc3cq7sb. Researchers argue that participation requirements in cancer clinical trials are too restrictive.

Wechsler, Jill , “FDA Examines Eligibility Criteria in Clinical Trial Design and Product Development,” Applied Clinical Trials, April 24, 2018, https://tinyurl.com/y7zpc75p. A recent U.S. Food and Drug Administration (FDA) workshop on clinical trials led regulators and researchers to re-examine enrollment guidelines.

Increasing Transparency

Baum, Stephanie , “Which pharma companies are the most transparent with clinical trial data?” MedCity News, Dec. 9, 2017, https://tinyurl.com/y7bwajyj. Johnson & Johnson and Sanofi/Genzyme are the most transparent pharmaceutical companies with regard to their clinical trials, according to a 2017 study.

Fassbender, Melissa , “Transparency on trial: How to navigate FDAAA 801 final rule implementation and compliance,” Outsourcing-Pharma.com, April 6, 2018, https://tinyurl.com/y7htnls6 A new FDA rule allows the agency to fine sponsors of clinical trials who fail to report their results.

Kirsh, Danielle , “FDA enhances the transparency of clinical trials,” Mass Device, April 17, 2018, https://tinyurl.com/yac7qod7. The FDA's new Clinical Data Summary Pilot Program increases transparency about clinical trials, providing more information than the agency's typical summaries.

Precision Medicine

Facher, Lev , “NIH opens nationwide enrollment for huge precision medicine initiative,” Stat, May 1, 2018, https://tinyurl.com/yd7yyg8l. A new National Institutes of Health initiative is collecting comprehensive health profiles of 1 million Americans, with the goal of better understanding precision medicine, which tailors treatment for individuals based on medical history, genetics, behavior and other factors.

Semigran, Marc , “Why Cardiology Is the Next Frontier for Precision Medicine,” Genetic Engineering and Biotechnology News, April 15, 2018, https://tinyurl.com/y73n8sq4. Cardiovascular disease causes more fatalities than any other, but the expansion of precision medicine could lead to treatment breakthroughs, says a chief medical officer.

Shaw, Jonathan , “Targeting Cancer,” Harvard Magazine, May-June 2018, https://tinyurl.com/y867fluc. Precision medicine is proving its potential to treat cancer, according to the managing editor of Harvard Magazine.

Right to Try Movement

“A Better Way to Provide a ‘Right to Try,’” Bloomberg, Feb. 12, 2018, https://tinyurl.com/y7u72uwn. Excluding the FDA from the process of considering whether terminally ill patients should receive experimental treatments, called the Right to Try, could cause more harm than good, says the Bloomberg Editorial Board.

Marangos, Paul J. , “‘Right to try’ efforts have been timid and poorly conceived,” The Hill, April 17, 2018, https://tinyurl.com/yc7hfnl4. Efforts to improve access to experimental medical treatments for terminally ill patients have been lackluster, says a biomedical researcher and inventor.

Roubein, Rachel , “Experimental drugs bill runs aground despite Trump, Pence support,” The Hill, April 26, 2018, https://tinyurl.com/yawjz3qn. Two Right to Try bills have deadlocked in the House and Senate amid concerns from House Democrats that both diminish the FDA's authority.

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Contacts

American Society of Clinical Oncology
2318 Mill Road, Suite 800, Alexandria, VA 22314
703-299-0158
www.asco.org
A network of nearly 45,000 oncology professionals that supports cancer research and education and promotes quality patient care.

Association of Clinical Research Organizations
1990 K St., N.W., Suite 401, Washington, DC 20006
202-464-9340
www.acrohealth.org
Conducts clinical trials in more than 140 countries for the pharmaceutical industry.

ClinicalTrials.gov ;
https://clinicaltrials.gov
A searchable registry and results database of federally and privately supported clinical trials conducted worldwide; provides information about the trials' purposes, who may participate, locations and phone numbers.

Clinical Trials Transformation Initiative
300 W. Morgan St., Suite 800, Durham, NC 27701
919-668-3437
www.ctti-clinicaltrials.org
An association of patient advocacy groups, professional societies, academic institutions and other groups working to improve clinical trials.

National Institutes of Health
9000 Rockville Pike, Bethesda, MD 20892
301-496-4000
www.nih.gov
A U.S. Health and Human Services Department agency that conducts and sponsors medical research.

Pharmaceutical Research and Manufacturers of America
950 F St., N.W., Suite 300, Washington, DC 20004
202-835-3400
www.phrma.org
A trade group that lobbies on behalf of leading pharmaceutical companies.

Public Citizen
1600 20th St., N.W., Washington, DC 20009
202-588-1000
www.citizen.org
A consumer group with a health and safety program that advocates banning or relabeling unsafe or ineffective drugs and medical devices.

ResearchMatch;
https://www.researchmatch.org
A free, secure, NIH-funded registry to connect people searching for studies or clinical trials and researchers seeking participants for their studies.

Tufts Center for the Study of Drug Development
75 Kneeland St., Suite 1100, Boston, MA 02111
617-636-2170
https://csdd.tufts.edu
A research center at Tufts University School of Medicine that monitors and reports on the development, regulation and utilization of new drugs and biopharmaceuticals.

U.S. Food and Drug Administration
10903 New Hampshire Ave., Silver Spring, MD 20993
888-463-6332
www.fda.gov
A Department of Health and Human Services agency that regulates medical products and drugs based on data from clinical trials.

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Footnotes

[1] Aimee Swartz, “Cancer clinical trials exclude many desperate patients. Should that change?” The Washington Post, Dec. 17, 2017, https://tinyurl.com/y8zrjhtd.

[2] Danielle Lavieri, “INC Research and CISCRP Launch ‘Inspiring Hope’ Ideathon to Boost Community Involvement in Raising Awareness of Clinical Research,” Center for Information and Study on Clinical Research Participation, May 20, 2016, https://tinyurl.com/yc7efjp7.

[3] Joseph M. Unger et al., “The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies,” ASCO Educational Book, 2016, pp. 186–188, https://tinyurl.com/yazpo45d.

[4] Grant D. Huang et al., “Clinical trials recruitment planning: A proposed framework from the Clinical Trials Transformation Initiative,” Contemporary Clinical Trials, March 2018, p. 74, https://tinyurl.com/y8ugc4tx.

[5] Barry Gertz, “Impact of the Crisis in Clinical Research on New Drug Development,” American Federation for Medical Research, 2010, p. 20, https://tinyurl.com/y73msfcc.

[6] “Public Perception of Clinical Trials,” Research!America, July 2017, https://tinyurl.com/y9tkbmau.

[7] Unger et al., op. cit., p. 187; “Poor physician and nurse engagement driving low patient recruitment,” Tufts Center for the Study of Drug Development, February 2017, https://tinyurl.com/y8n4hlqw.

[8] Ibid., Unger.

[9] Marita Golden “African Americans are more likely than whites to develop Alzheimer's. Why?” The Washington Post, June 1, 2017, https://tinyurl.com/y7wzzv8h.

[10] “Clinical Trials: Survey Data of Minority Populations,” Research!America, July 2017, https://tinyurl.com/ycghljex.

[11] Maggie Fox, “Speed Up Drug Approvals? FDA Already Did,” NBC News, Feb. 1, 2017, https://tinyurl.com/yadrjosa.

[12] “GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data,” Department of Justice, July 2, 2012, https://tinyurl.com/hx5hlvw.

[13] “HHS takes steps to provide more information about clinical trials to the public,” National Institutes of Health, Sept. 16, 2016, https://tinyurl.com/y8lfrmsa.

[14] “New automated clinical trials tracker shows around half of all trials have not published results, shines a spotlight on the worst companies and universities,” AllTrials, November 2016, https://tinyurl.com/y7m3of5n.

[15] “Who's sharing their clinical trial results?” FDAAA TrialsTracker, as of May 6, 2018, https://tinyurl.com/y8aez9dr; “About the FDAA TrialsTracker,” FDAAA TrialsTracker, https://tinyurl.com/ya2vkdnx.

[16] “Clinical Trial Data Transparency,” PhRMA, https://tinyurl.com/yc8krxu2.

[17] Janet Woodcock, “FDA's New Pilot Program Aims for More Transparency about New Drug Approvals,” U.S. Food and Drug Administration, March 19, 2018, https://tinyurl.com/y9yhef92; “Drug Approval Package: ERLEADA (apalutamide),” U.S. Food and Drug Administration, March 29, 2018, https://tinyurl.com/ycha9out.

[18] Tianjing Li, “Tianjing Li: What's not shared — building on the FDA's transparency momentum,” The BMJ Opinion, Jan. 31, 2018, https://tinyurl.com/yaj3od6o.

[19] Swartz, op. cit.

[20] Julia A. Beaver, Gwynn Ison and Richard Pazdur, “Reevaluating Eligibility Criteria — Balancing Patient Protection and Participation in Oncology Trials,” The New England Journal of Medicine, April 20, 2017, p. 1504, https://tinyurl.com/yb33bqtg.

[21] Ibid., pp. 1504–1505.

[22] Edward S. Kim et al., “Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement,” Journal of Clinical Oncology, Oct. 2, 2017, p. 1, https://tinyurl.com/y8o2x9ea.

[23] Swartz, op. cit.

[24] A. Srikanthan et al., “Evolution in the eligibility criteria of randomized controlled trials for systemic cancer therapies,” Cancer Treatment Reviews, December 2015, p. 68, https://tinyurl.com/y9kp9ctr; Sandra Garcia et al., “Thoracic Oncology Clinical Trial Eligibility Criteria and Requirements Continue to Increase in Number and Complexity,” Journal of Thoracic Oncology, October 2017, pp. 1489–95, https://tinyurl.com/y89d2b3l.

[25] Beaver, Ison and Pazdur, op. cit.

[26] Elaine Silvestrini, “Studies: Major Flaws Found in Some Drug Approvals,” Drugwatch, April 17, 2018, https://tinyurl.com/y9o9vf29; Chul Kim and Vinay Prasad, “Cancer Drugs Approved on the Basis of a Surrogate End Point and Subsequent Overall Survival: An Analysis of 5 Years of US Food and Drug Administration Approvals,” JAMA Internal Medicine, December 2015, pp. 1992–1994, https://tinyurl.com/y8dr87co.

[27] Kim and Prasad, ibid., p. 1994.

[28] Dennis Thompson, “Is FDA Taking Close Enough Look at Fast-Tracked Drugs?” HealthDay, Aug. 15, 2017, https://tinyurl.com/y9k7taea.

[29] Huseyin Naci, Katelyn R. Smalley and Aaron S. Kesselheim, “Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration,” JAMA, Aug. 15, 2017, https://tinyurl.com/ydzbcgn6.

[30] Iain Milne, “Who was James Lind, and what exactly did he achieve?” The James Lind Library, 2012, https://tinyurl.com/yb4wdpxe.

[31] Ibid.

[32] Marcia L. Meldrum, “A Brief History of the Randomized Controlled Trial: From Oranges and Lemons to the Gold Standard,” Science Direct, August 2000, p. 748, https://tinyurl.com/yajsnaav.

[33] Ibid.

[34] Ibid.

[35] Ibid.

[36] Ibid.

[37] “A Short History of the National Institutes of Health,” National Institutes of Health, pp. 1–3, https://tinyurl.com/y9kuounr.

[38] Harry M. Marks, The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900–1990 (1997), pp. 23–24.

[39] Ibid., pp. 32–34.

[40] Ibid., pp. 35–37; Suzanne White Junod, “FDA and Clinical Drug Trials: A Short History,” U.S. Food and Drug Administration, Feb. 1, 2018, https://tinyurl.com/yazxry74.

[41] Marks, op. cit., pp. 74–75.

[42] Iain Chalmers et al., “The advent of fair treatment allocation schedules in clinical trials during the 19th and early 20th centuries,” The Journal of the Royal Society of Medicine, May 1, 2012, p. 224, https://tinyurl.com/y9o7gruz.

[43] Junod, op. cit.; “The History of Clinical Research: A Timeline Provided by IMARC,” IMARC Research, p. 6, https://tinyurl.com/ybz4z7va.

[44] Junod, ibid.

[45] Marks, op. cit., pp. 71–72.

[46] Junod, op. cit.

[47] Ibid.

[48] Meldrum, op. cit., p. 752.

[49] Ibid., p. 753.

[50] Marchia Meldrum and DeWitt Stetten, “‘A calculated risk’: the Salk polio vaccine field trials of 1954,” BMJ, Oct. 31, 1998, https://tinyurl.com/y9sy24rs.

[51] Junod, op. cit.

[52] Laura E. Bothwell et al., “Assessing the Gold Standard — Lessons from the History of RCTs,” The New England Journal of Medicine, June 2, 2016, p. 2175, https://tinyurl.com/ydaazl7k.

[53] Junod, op. cit.

[54] Ibid.

[55] Bothwell, op. cit.

[56] “Peter Buxton — Public Health Service Defendant,” Whistleblower Policy, https://tinyurl.com/ydx83lf7.

[57] “How Tuskegee Changed Research Practices,” CDC, last updated Feb. 22, 2017, https://tinyurl.com/y9tnhkgh.

[58] Ibid.

[59] “Frequently Asked Questions About Institutional Review Boards,” American Psychological Association, https://tinyurl.com/ydh9evvg.

[60] Meredith Cohn, “Industry funds six times more clinical trials than feds, research shows,” The Baltimore Sun, Dec. 15, 2015, https://tinyurl.com/hnmr7zj.

[61] Ibid.

[62] Bothwell, op. cit.

[63] “History, Policies, and Laws,” U.S. National Library of Medicine, last reviewed July 2017, https://tinyurl.com/y9ekhfz6.

[64] “Preventing Patient Harm in 21st Century Cures,” Public Citizen, https://tinyurl.com/ya4whrlk.

[65] Reshma Ramachandran and Zackary Berger, “21st Century Cures Act will distort the meaning of ‘FDA approved,’” Stat, Dec. 5, 2016, https://tinyurl.com/yawadzvh.

[66] “FY 2018 R&D Appropriations Dashboard,” American Association for the Advancement of Science, March 23, 3018, https://tinyurl.com/yb4xg5qh.

[67] “U.S. Investments in Medical and Health Research and Development 2013–2016,” Research!America, Fall 2017, p. 4, https://tinyurl.com/yc398t33.

[68] Ibid., pp. 4, 6.

[69] “NIH Funding Fewer Clinical Trials, Study Suggests,” Johns Hopkins Bloomberg School of Public Health, Feb. 13, 2018, https://tinyurl.com/ycxrqn8n.

[70] Ibid.

[71] Ibid.

[72] Ibid.

[73] David Malakoff, “First take: Trump's 2019 budget not as disastrous for science as it first appears,” Science, Feb. 12, 2018, https://tinyurl.com/y78ygfc8.

[74] Mary Jo Lamberti and Kenneth Getz, “Profiles of New Approaches to Improving the Efficiency and Performance of Pharmaceutical Drug Development,” Tufts Center for the Study of Drug Development, May 2015, p. 1, https://tinyurl.com/y7vzj7qn.

[75] “About Lung-Map,” Lung-Map, https://tinyurl.com/y9yfcwka.

[76] George Weiner, “Holden the Line on Cancer,” University of Iowa, Aug. 1, 2014, https://tinyurl.com/yc5zojnu.

[77] Howard West, “Novel Precision Medicine Trial Designs: Umbrellas and Baskets,” JAMA Oncology, March 2017, https://tinyurl.com/yckztcbt.

[78] Erin Mershon, “Koch-backed group launches new national ad push to advance ‘right-to-try’ legislation,” Stat, April 26, 2018, https://tinyurl.com/y8gmvzlf.

[79] Peter Lurie, “Exploring a Right to Try for Terminally Ill Patients,” Food and Drug Administration, Sept. 22, 2016, https://tinyurl.com/y78ouaf5.

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About the Author

Barbara Mantel, is a freelance writer in New York City. She has been a Kiplinger Fellow and has won several journalism awards, including the National Press Club's Best Consumer Journalism Award and the Front Page Award. She was a correspondent for NPR and the founding senior editor and producer for public radio's “Science Friday.” She holds a B.A. in history and economics from the University of Virginia and an M.A. in economics from Northwestern University.

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