Clinical trials to evaluate new drugs are typically built around one design, the randomized controlled trial, but this method has come under scrutiny in recent years for being expensive, lengthy, and cumbersome. In this podcast you’ll hear from experts asking if alternative designs would be better for determining the safety and efficacy of new therapies.
This podcast was produced following a conference on this topic held in partnership between the NYU School of Medicine and The New York Academy of Sciences. It was made possible with support from Johnson & Johnson.
From research in the biophysics of RNA to advances in cancer immunotherapy and vaccine antibodies.
Published October 1, 2017
By Kari Fischer, PhD
Jeffrey V. Ravetch, MD, PhD, Theresa and Eugene M. Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology at The Rockefeller University, received the 2017 Ross Prize in Molecular Medicine — established in conjunction with the Feinstein Institute for Medical Research and Molecular Medicine — for his discovery of how antibodies generate a wide range of immune responses: through Fc receptors.
The path to this accolade was a hard won fight. Ravetch’s work challenged a dogma of immunology, and consequently he spent his first 20 years as an independent investigator in relative isolation. When asked how he would encourage other researchers to drive through such a period, his response was emblematic of his career.
“I think the point of science is that you never stop learning. You have to continually push yourself to be uncomfortable in a new field, and potentially get up there and say something that’s wrong,” Ravetch says.
From left to right:Kevin J. Tracey, MD, President and CEO, The Feinstein Institute for Medical Research; Jeffrey V. Ravetch, MD, PhD, Theresa and Eugene M. Lang Professor, The Rockefeller University; Robin Ross, Board of Directors, The Feinstein Institute for Medical Research; Klass Kärre, MD, PhD, Professor, Karolinska Institutet.
Raised in the Sputnik Age, Inspired by Scientists
Raised in the age of Sputnik, a young Ravetch elected scientists instead of sportsman as his heroes — absorbing the biographies of Louis Pasteur and Albert Einstein. Recounting his first experiments in his high school basement, without any guidance, Ravetch laughed, “It’s remarkable how naïve I was.” He studied the embryonic development of zebrafish, using a homemade frame to collect the embryos and a borrowed microscope.
Transitioning into more formative research, Ravetch delved into the biophysics of RNA folding as an undergraduate. He subsequently earned an MD so he could apply his findings to human disease, a PhD in bacterial genetics and a postdoc employing molecular biology to study antibody recombination. Ravetch had no one love in science, except for science itself.
When first pursuing antibody receptors that may mediate inflammatory responses, he encountered either indifference or bewilderment as the mechanism for this process already existed: through the complement system. But Ravetch had the benefit of not yet being an immunologist — he lacked the tunnel vision that can form when studying one field — and instead was driven by a basic interest in the structure and function of Fc receptors.
Groundbreaking Work in the Role of Antibodies in Vaccine Development
His group eventually demonstrated that the Fc region of antibodies can either induce or suppress an immune response by binding to the activating or inhibitory versions of Fc receptors on immune cells — without complement. This was groundbreaking, and opened many questions on how antibodies can fine tune immune activation or suppression.
Ravetch found one answer through a bit of serendipity: he was invited to the right conference. Knowing little about intravenous gamma globulin (IVIG) therapy, he flew to California to attend a clinical meeting on the topic. IVIG is the administration of antibodies isolated from donated blood, and is given as an anti-inflammatory.
How IVIG worked was unknown, and Ravetch heard an abundance of theories at the conference. None were satisfying, and Ravetch had a new question to chase.
He returned to the lab, and found that IVIG’s therapeutic effects occurred through the inhibitory Fc receptor. Moreover, the antibodies’ ability to induce an inhibitory response, and dampen inflammation, resulted from the presence of specific carbohydrates attached to their Fc region. The presence and structure of those carbohydrates dictates the type of Fc receptor with which they can bind. Reigniting his undergraduate training on intricate molecular relationships, Ravetch went back to “school.”
“Nothing prepared us for this kind of interaction, and it was fascinating. It was one of those wonderful Christmas vacations where, for two weeks, I just sat and read up on carbohydrates,” he says.
Extending into Cancer Immunotherapy, Improved Vaccine Design
Beyond scholarly pursuits, these discoveries influence therapy. Ravetch’s findings on Fc receptors had not yet gained traction at the advent of therapeutic antibodies, and pharmaceutical companies focused on the antigen-binding variable region, not the Fc.
This carried into the pioneering field of cancer immunotherapy, where many promising agents were successful in mice, but then failed in the clinic. There, Ravetch cites a lack of attention to the Fc, and he now collaborates with companies to share his expertise and develop better therapeutic antibodies for the treatment of cancer, inflammation and infectious diseases.
Lately, Ravetch is branching into a new area with vaccines, exploring how antibodies offer protection upon vaccination, and how that knowledge could improve vaccine design — perhaps yielding a universal flu vaccine. Beyond that, Ravetch does not have a plan, but this is true to his style.
“I don’t really know what’s going to happen in the next weeks or months. There’s a certain expectation based on what you’re doing, but if you don’t see unexpected observations, the fun is gone,” he says. “I’m looking forward to the unknowns.”
The enterprise of drug development is a crucial lifeline for patients and their families. Those who need new and better treatment options depend on researchers to deliver safe and effective therapies as quickly as possible, meaning experimental drugs must first be tested on human volunteers before they can be approved for widespread use.
Since the mid-twentieth century, the randomized controlled trial (RCT) has been considered the gold-standard in research design because of its ability to overcome bias and yield high-quality evidence. But it comes at a steep cost: The average new drug requires six to eight years of human testing and $100 million to fund the clinical trial phase alone. Moreover, conducting an RCT is not always feasible or moral, such as during a pandemic or in the case of a very rare disease.
In such cases, alternative trial designs may produce faster and cheaper results, but in doing so, they must not compromise appropriate levels of standards of safety and efficacy, say regulators, patients, and insurers. While more rapid development is critical to save lives, difficult questions remain about how to tread this delicate balance.
On June 21 – 22, 2017, the Academy convened a colloquium at which academic and pharmaceutical researchers, federal regulators, bioethicists, executives, patient advocates, and lawyers met to discuss the relevance of the randomized controlled trial as the default model for human subject research. Talks focused on the history of the RCT, the ethics and use of alternative trial designs, the risks of foregoing traditional tools, the role of patient advocacy, lessons learned from a recent case study, and the importance of innovation in reforming a flawed system.
With the success of emerging interventions like genomic therapy and immunotherapy, a cultural conversation has opened up around issues such as determining how clinical trials should be designed in this new era, who may participate in research, and when promising therapies should reach the market. Formulating answers to these urgent questions could benefit millions of patients and reshape the future of medicine.
Speakers
Alison Bateman-House, PhD, MPH, MA NYU School of Medicine
Luciana Lopes Borio, MD U.S. Food & Drug Administration
Timothy Caulfield, LLM, FRSC, FCAHS University of Alberta
Anne Cropp, PharmD Early Access Care, LLC
George D. Demetri, MD Dana-Farber Cancer Institute
Rebecca Susan Dresser, JD Washington University in St. Louis
Susan S. Ellenberg, PhD University of Pennsylvania
Howard Fingert, MD, FACP Takeda Pharmaceuticals
Pat Furlong Parent Project Muscular Dystrophy
Barry J. Gertz, MD, PhD Clarus Ventures
Edward M. Kaye, MD Sarepta Therapeutics
Nancy M.P. King, JD Wake Forest School of Medicine
Clifton Leaf Fortune
Holly Fernandez Lynch, JD, BE The Petrie-Flom Center for Health Law Policy, Biotechnology and Bioethics at Harvard Law School
Susan E. Lederer, PhD University of Wisconsin School of Medicine and Public Health
Andrew McFayden The Isaac Foundation
Jane Perlmutter, PhD Gemini Group
Vinay Prasad, MD, MPH Oregon Health and Science University
Amrit Ray, MD Johnson & Johnson
Jane Reese-Coulbourne, MS, ChE MK&A
Christopher Robertson, PhD, JD University of Arizona
Matthew D. Rotelli, PhD Eli Lilly and Company
Eric H. Rubin, MD Merck & Co., Inc.
David Scheer Scheer & Company, Inc.
J. Russell Teagarden NYU School of Medicine Working Group on Compassionate Use & Pre-Approval Access
John (L.P.) Thompson, PhD Columbia University
Meg Tirrell CNBC
Andrea B. Troxel, ScD NYU School of Medicine
Ellis Frank Unger, MD U.S. Food & Drug Administration
Steve Usdin BioCentury
Joanne Waldstreicher, MD Johnson & Johnson
Jeffrey S. Weber, MD, PhD NYU Langone Medical Center
Charles Weijer, MD, PhD Western University
Robert Walker, MD U.S. Department of Health and Human Services
Sponsors
This symposium was made possible with support from
Presented by
Meeting Reports
History and Contribution of Randomized Controlled Trials to Public Health
Speakers
Susan S. Ellenberg, Panelist University of Pennsylvania
Howard Fingert, Panelist Takeda Pharmaceuticals
Susan E. Lederer, Panelist University of Wisconsin School of Medicine and Public Health
Jane Perlmutter, Panelist Gemini Group
Arthur Caplan NYU School of Medicine
Panel Discussion History and Contribution of Randomized Controlled Trials to Public Health
Highlights
American laws regarding drug testing transformed in the 1960s in response to crisis.
New epidemics and targeted genomic therapy are prompting re-evaluation of the RCT.
Industry sponsors have a responsibility to uphold data quality.
A tension may exist between statistical endpoints and patient experiences.
History lessons
The opening panel set the stage for the role RCTs have played in the history of medical research. Susan Lederer, a professor of medical history and bioethics at the University of Wisconsin, described how clinical trials first came to be. In the 1760s, James Lind was a ship surgeon in the British navy faced with a rash of scurvy cases.
In a bid to stop the outbreak, he divided twelve sailors into groups of two, rotating each through different sets of treatments. The groups tried sea water, sulfuric acid, vinegar, cider, a tamarind paste, and oranges and lemons. When that last treatment proved effective, Lind realized he had hit upon a cure.
But officially randomizing treatment into a control arm and a trial arm didn’t gain traction until the mid-twentieth century, when World War II prompted a massive influx of federal dollars for research, and the pharmaceutical industry began to transform American medicine. In the early 1960s, after many pregnant women took the drug thalidomide, which caused fetal deaths and birth defects, Congress established laws calling for “adequate and well-controlled” studies that demonstrated efficacy as well as safety before drugs could be approved.
By the 1970s and 80s, the RCT had become the gold standard, said Arthur Caplan, a bioethicist at the NYU School of Medicine. But just two decades later, criticism emerged during the HIV epidemic, when many patients pushed back on ethical grounds against being randomized, contending that scientific advancement should not come at the cost of their own lives. While some patient groups praised the RCT model, some observers, like prominent physician Marcia Angell, called into question researchers’ “slavish adherence” to the RCT at the expense of compassion for individual sufferers.
In the current era of epidemics like Ebola and Zika, and the increasing prevalence of targeted genomic therapies, the relevance of the standard RCT has been called into question with renewed urgency. Some situations, Caplan said, don’t permit the time or expense of a standard RCT. That’s a point which has raised substantial debate, but some argue that patients may be too sick to participate, the need for treatment may be immediate, the number of sufferers too small, or the ability to maintain oversight too unrealistic.
Jane Perlmutter, a patient advocate, offered additional concerns about RCTs, including limitations on generalizability if trial subjects don’t comply with the protocol, and if eligibility requirements narrow the scope of the testing population.
“This gold standard is not so terrific,” she declared. “We need to innovate.”
Patients also don’t like to be guinea pigs, she noted, suggesting one “baby step,” towards innovation could be allowing patients to choose to join the experiment or control group, rather than be blinded and randomized. Still, randomizing some patients in is important to preventing bias and leading to generalizable findings. In such a design, researchers must carefully assess the data to ensure that the randomized subjects and the self-chosen subjects show no misleading discrepancies. As long as their results align, this type of study can be both efficient and effective.
At the same time, Howard Fingert, senior medical director at Takeda Pharmaceuticals, said that the management of big data is a major responsibility and opportunity for industry sponsors no matter the trial design. Mechanisms for data sharing can improve understanding in trials that are single-armed, propensity-matched (meaning those driven by a statistical score that estimates a treatment’s effectiveness), or underpowered (meaning those statistically unlikely to distinguish a treatment effect from pure luck due to a low sample size).
And upholding data that is reflective of reality is crucial, he said. For example, if a primary endpoint in a study fails, investigators may look for a positive secondary endpoint that wasn’t originally in the protocol—a practice he called “ubiquitous but not legitimate.”
Caplan asked whether fear of adverse outcomes is hindering innovation, citing the 1999 death of an 18-year-old in a clinical trial for gene therapy, which proved a major setback for the entire burgeoning field. Susan Ellenberg, a professor of biostatistics at the University of Pennsylvania, noted that risk aversion is even more common now, as social media reinforces people’s negative beliefs about the prevalence of dire medical events, like vaccine toxicity. But 37 states have passed right-to-try laws, Perlmutter pointed out, which permit terminally ill patients to volunteer for experimental therapies.
Finally, the panelists discussed how the very notion of efficacy has evolved. Decades ago, patients were asked if they were feeling better after an intervention, but now the focus is on objective endpoints—sometimes to a fault, according to Perlmutter. She questioned whether an outcome such as a shrinking cancer tumor, for example, is truly meaningful if the patient’s quality of life remains unaffected. Caplan reminded the group that in dialysis programs for end-stage renal disease in the 1970s, one measure of success was whether patients could return to work. But Ellenberg added that patient improvement and high-quality data are not mutually exclusive.
“Looking for objectivity doesn’t exclude those endpoints,” she said.
Luciana Lopes Borio, Panelist U.S. Food and Drug Administration
Barry J. Gertz, Panelist Clarus Ventures
Andrea Troxel, Panelist NYU School of Medicine
Charles Weijer, Moderator Western University
Panel Discussion Beyond RCTs — Assessing the Need for Alternatives
Highlights
Choosing between a standard RCT and a non-RCT alternative can be a false dichotomy.
FDA states that all patients deserve the same evidentiary and regulatory standard.
Tension exists between targeting therapies to the right patient population and understanding drug safety and efficacy.
Innovation without compromise
Moderator Charles Weijer, a bioethicist at Western University, kicked off the discussion by asking panelists to offer up important lessons about clinical trials from the past. Barry Gertz, a partner at Clarus, pointed to randomization as the key to reducing bias, and a reason why the RCT ought to remain the default design for testing new agents. Despite its heavy costs, he argued, the overall societal burden would be even higher without it, citing the example of a new device tested for severe hypertension. It produced what seemed at first to be miraculous results—until a subsequent RCT proved it no better than a sham procedure.
“If you don’t test with adequate rigor,” he warned, “society will pay a very substantial price if it’s not as effective as it’s billed to be.”
Luciana Borio, acting chief scientist at the FDA, agreed that classic RCTs still deserve a primary place in the medical ecosystem.
“Nobody has said, ‘I regret doing an RCT,’” she said. “History has played out the other way around; ‘we didn’t know and had to live with the consequences.’”
Even in cases of public health emergencies like Ebola, when some scientists deem RCTs impractical, she maintained that such situations especially demand informative studies.
“We have to be better prepared for the next epidemic,” she added. “We can’t say it’s too hard to do it.”
Weijer commented on the importance of avoiding a false dichotomy between RCTs and alternatives that are still capable of incorporating randomization into their designs. For example, Borio mentioned the ring study carried out during the Ebola crisis, in which groups of people known to be in contact with a patient—those forming a so-called “ring” around the infected person—were randomized to receive a new vaccine either immediately or after a three-week delay.
Andrea Troxel, a professor of population health and biostatistics at NYU, agreed that randomization in some capacity is necessary for the generation of high-quality knowledge, even if a standard RCT “is not always the answer.”
Weijer then raised the complex issue of whether rare diseases necessitate a lower standard of evidence for drug approval, given the lack of patients available for clinical trials. While Troxel said that “sufficient evidence” would not be possible to attain in a standard RCT, others disagreed. Gertz pointed to the approval of a drug for spinal muscle atrophy, the most common genetic cause of early demise in infants. An RCT was carried out on just 81 patients using a sham placebo administered to the spinal fluid, with results showing that the drug yielded profound increases in motor activity.
“It benefited a very small number, but even in that rare disease, the RCT provided some real evidence of benefit and is now available,” he said.
Regarding common diseases, the panelists disagreed on whether a social imperative to accelerate development justifies a lower evidentiary standard. Borio cautioned against the temptation to take short cuts, and said that all patients deserve the same high regulatory standard, while Troxel similarly warned of the “unintended consequences” of rushing new therapies out to desperate patients.
But at that moment, patient advocate Jane Perlmutter spoke up from the audience, declaring that patients with terminal illnesses want to take risks. “I don’t think we need to lower the bar, but we need to have innovative approaches to deal with deadly diseases,” she said. Gertz suggested that one potential solution would be for the FDA to grant a drug provisional approval using an intermediate or surrogate endpoint, with later testing to confirm the findings.
But if those findings failed to hold up, withdrawing such a drug from the market would be difficult, due to a backlash from patients still demanding access to the drug. He said this scenario has happened once in oncology and “it wasn’t pretty.”
In the unique case of biologically targeted therapy, Weijer posed the intriguing question as to whether the science has evolved to such point that an RCT is not needed to evaluate a drug’s effectiveness. Gertz acknowledged that studies with driving mutations in oncology are typically single arm, but that a control group is implicit in the standard of care response rates. He also maintained that a randomized trial would be needed eventually to determine safety as well as efficacy.
All the panelists agreed that helping the diverse range of patients who exist in the real world is crucial, and requires testing beyond narrow subsets who don’t reflect the larger population. More recently, pragmatic trials—which more realistically mimic day-to-day practice settings—are gaining traction, said Troxel.
Such trials aim to clarify how effective a recommended therapy might be, as opposed to explanatory trials, which aim to elucidate mechanisms of action in a new agent. Yet, “those two goals are not necessarily in conflict,” she said. A trial might be explanatory at first, with small numbers and a strict inclusion criteria, then broadened to test the therapy on a wider group.
Borio lamented that researchers don’t learn from most patient encounters because of a lack of access to studies. Today, the practice of medicine often takes place separately from the world of research, so when sick patients visit the doctor, their cases are not analyzed to improve the effectiveness of treatments for others. And those who do participate in studies often fail to represent important demographic subgroups.
Currently, the typical participant is a young, white male who lives near a metropolitan area. Borio would like studies to systematically include patients who are not usually included, like those in rural areas, minorities, babies, and pregnant women. Her dream is for every person in the medical system to be able to enroll in a clinical trial.
“There’s no national trial infrastructure in this country, like highways,” she said. “But we need it so we can make the most use of all the knowledge.”
Doing so, however, she acknowledged would require a major shift in how doctors are educated about clinical trials and how patients view the riskiness of participating in research. Many patients decline to participate because they view research as inherently riskier than regular medicine, which is not necessarily true.
Expert Opinion Pharmacotherapy 16(9):1275-9, Jun 2015.
Finding the Right Balance in Learning about Therapies
Speakers
Robert Califf Duke University
Audience Q&A with Robert Califf
Highlights
There are clear benefits to combining research with clinical practice.
RCTs and alternative trials could be combined and run continuously.
The current clinical trial system is deeply flawed and too expensive.
Data sharing among health care systems will speed evaluation and development.
Asking the right questions
The future of human experimentation is at a crossroads. Sick and dying patients need treatment options as quickly as possible, but rushing out new therapies will not necessarily benefit them.
The real issue, said keynote speaker Robert Califf, is how to accelerate drug development but also “get it right.” The current clinical trial enterprise has “gone awry,” he said, calling it unnecessarily expensive.
Califf, a cardiologist and former commissioner of the FDA from 2016 to 2017, charged the system fails patients by not asking all the important questions. “It’s not that clinical trials are too hard, it’s that there are questions not even being asked because it’s so costly,” he said.
A schism has developed in medicine, between those who think human experimentation should be conducted within the context of daily practice and those who feel it should remain separate from it. In Califf’s view, human experiments benefit when combined with insights of clinicians, but the layers of oversight and the risk of punitive action dissuades doctors from participating in research. He criticized what he called common myths about RCTs: that they must exclude patients who represent the likeliest use of therapies, and that clinical trials are risky compared with routine care.
“There’s no reason you can’t enroll real-world clinical patients in a trial,” he said.
He also dismissed the notion that doctors regularly review evidence and make the best decisions for their patients—simply because statistically valid evidence often doesn’t exist in medicine. In fact, he said, many practice recommendations are not based on high-quality evidence, such as the CDC’s recent guidelines for prescribing opioids. Unlike the rigorous approach codified in research studies, much of medical practice is rooted in observational and historical data, leaving doctors with a limited set of tools.
His solution is to run RCTs in combination with alternatives, such as pragmatic trials, to reduce the cost and enable better generalizability from the start. In the early phases of therapeutic development, he suggested randomizing from the first patient — “the quickest way to get treatment to patients even with rare diseases.”
Then, in later phases, every interaction with patients would be logged in a digital database. He urged a national paradigm shift toward the sharing of such data across health care networks. Such an effort would be in keeping with the drive to create incentives for health systems to work together that was written into the 21st Century Cures Act, which was signed into law in December 2016, and the user fee reauthorization bill currently working its way through Congress.
He envisions moving away from inefficient one-off studies, done in a parallel track to clinical practice with passive surveillance, to active surveillance, for instance by collecting information on millions of patients in a central database embedded in the health care system, with broad data-sharing among providers. He discussed his involvement in PCORnet, the National Patient-Centered Clinical Research Network, which collects data across hospitals, doctor’s offices, and community clinics in an attempt to help guide healthcare decisions.
He also urged patients to push academic health systems to stop hoarding data, positing that if the medical world shared the business world’s mentality of persistent data collection, progress would accelerate.
“When you do a Google search, you’re participating in up to ten randomized trials,” he noted.
The bottom line, he concluded, is not to abandon RCTs, but to maintain continuous and constant observation as health care is delivered. Just as Google analyzes its data nonstop to improve user experience and anticipate search queries, medicine ought to catalogue and interpret its abundance of real-world data to bring to light the best treatment options for patients.
Weighing the Risks of Randomized Controlled Trials and Alternatives
Speakers
Holly Fernandez Lynch, Panelist Petrie-Flom Center for Health Law Policy, Biotechnology and Bioethics at Harvard Law School
Amrit Ray, Panelist Johnson & Johnson
Matthew D. Rotelli, Panelist Eli Lilly and Company
Robert Walker, Panelist U.S. Dept. of Health and Human Services
Steve Usdin, Moderator BioCentury
Panel Discussion Weighing the Risks of RCTs and Alternatives
Highlights
Controversy surrounds the use of RCTs during public health emergencies.
Platform trials can reduce costs and increase efficiency.
Vulnerable populations need adequate access to clinical trials.
Increasing research participation is key to obtaining comprehensive data.
Maintaining equipoise
Genuine uncertainty about the comparative effectiveness of different interventions is the ethical foundation for randomized clinical testing, a concept known as equipoise. Moderator Steve Usdin, Washington editor of BioCentury, opened the discussion by asking panelists to weigh in on the challenges of striking equipoise during therapeutic development. If a given intervention is known to work, the researcher cannot in good conscience withhold it from test subjects, said Harvard bioethicist Holly Fernandez Lynch.
Robert Walker, acting chief medical officer of the Biomedical Advanced Research and Development Authority (BARDA) within the U.S. Department of Health and Human Services, discussed the challenges of maintaining equipoise during the Ebola crisis.
“There was a sense that you can’t conduct a clinical trial in the midst of an emergency response, but we saw that it was in fact feasible,” he said, citing three randomized vaccines trials carried out in Liberia, New Guinea, and Sierra Leone.
As to the private groups that granted some patients emergency access to treatment during the public health emergency—without a trial to gauge efficacy—Walker said, “It’s not even information…We really didn’t learn.”
Usdin asked the panelists to describe when to use RCTs versus alternatives. Amrit Ray, chief medical officer at Johnson & Johnson, posed a solution that would retain the benefits of randomization but reduce the costs and facilitate data sharing: integrated platform trials. In the current system, five companies might test five different drugs for the same disease in isolation. Instead, Ray proposed, what if those companies collaborated on one joint trial with a common control arm? This would lessen the burden of duplicate trials and patient recruitment, and allow for faster data collection to evaluate drugs, as with the innovative I SPY-2 trials in breast cancer.
Then Matthew Rotelli, a director at Eli Lilly, raised the challenge of how to broaden clinical trials to include vulnerable populations like children, “because if you don’t study them,” he said, “you have no way to guide their treatment.” Walker responded that BARDA has a legislative mandate to study all populations, and that special additional oversight for kids would only make the process more onerous. He stated that existing measures, including institutional review board review, are already responsible for ensuring proper informed consent.
Regarding novel trial designs, Usdin worried that even if the data persuades regulators to approve a drug, insurers still might not pay without the legitimacy conferred by a standard RCT. Ray responded that the comparison design of platform trials could potentially mitigate that risk.
Another new paradigm could emerge to meet serious unmet needs—allowing patients to risk taking a promising experimental drug faster in exchange for the sponsor collecting comprehensive data post-market. While Fernandez called this an “ideal world,” she was somberly realistic about its prospects. New laws would have to be passed, and sponsors would need to be held accountable.
Rotelli envisioned a future in which clinical trials never end. As new drugs come out, they are added to ongoing randomized platform trials for further study against known drugs. Less effective ones eventually get dropped, while electronic medical records facilitate the data collection. But obtaining and sharing that data would require a “dramatic shakeup of systems,” Fernandez said.
Right now, research participation requires robust informed consent, with autonomy prized as the highest value. It operates in a separate layer from clinical care, protected by institutional review boards that regularly review protocols to protect participants from exploitation.
An opposite model, in which data collection is routine, would require most patients to participate by default, rather than choosing to opt in.
“I don’t know that I would go to that end of the spectrum,” she said. “It’s so different from how we’ve done research, given concerns about historical abuses.”
Expecting compulsory participation makes many observers in the medical community uneasy. The twentieth century, after all, is filled with brazen examples of vulnerable subjects who were harmed or killed for the sake of science, including concentration camp victims and the cohort of African-American men infected with syphilis who, unbeknownst to them, were denied penicillin by Tuskegee researchers. Such infamous cases led to establishment of a set of morals and rules for human research participation via the 1947 Nuremberg Code and the 1979 Belmont Report, establishing the ethical pillars of autonomy and informed consent.
Unless such historical abuses fade in the collective consciousness, any future reforms that dial back the protection of individuals are unlikely to be popular.
Ethics and Patient Advocacy in Clinical Trial Design
Speakers
Rebecca Susan Dresser, Panelist Washington University in St. Louis
Andrew McFadyen, Panelist The Isaac Foundation
Jane Reese-Coulbourne, Panelist MK&A
J. Russell Teagarden, Panelist NYU School of Medicine Working Group on Compassionate Use & Pre-Approval Access
Alison Bateman-House, Moderator NYU School of Medicine
Panel Discussion Ethics and Patient Advocacy in Clinical Trial Design
Highlights
A cultural clash exists between patients and researchers.
Many specialists agree that clinical design could be improved by involving patient experts early on.
Early access programs allow patients to try experimental therapies outside of clinical trials.
Expanding inclusion criteria would allow more people to participate in research.
Balancing acts
When it comes to the policies and guidelines that govern drug development, patients and researchers often find themselves at odds, clashing over aspects such as trial design, compliance protocols, and early access. Differing motivations lie at the heart of the conflict, suggested moderator Alison Bateman-House, a bioethicist at NYU. Researchers want to help push science forward, while patients want access to therapies that will help them and their loved ones.
“When you’re a patient or a parent, [those with] the option of being in a trial think, ‘What would benefit me most?’” said Rebecca Susan Dresser, a cancer survivor and bioethicist at Washington University in St. Louis. “Altruism is low on the list.”
Many of those who can’t participate in trials struggle to persuade sponsors to let them try experimental therapies under the FDA’s program of expanded access, also known as compassionate use. Companies may be reluctant to participate in compassionate use in part because giving patients a drug outside of a trial means a lost opportunity to gain valuable data on safety and efficacy.
Advocacy groups, such as Andrew McFadyen’s Isaac Foundation, fight for access despite these concerns, because offering patients with rare diseases otherwise unavailable treatments can mean the difference between life and death.
“While RCTs are good at getting approval of drugs, it’s a hindrance in getting them to our children,” he said.
Patients and researchers should work together from the start of designing a trial so their goals can coincide, the panelists all suggested. Too often, Bateman-House said, patients are silent partners, which can translate into a protocol that’s too lengthy, intensive, or inconvenient. For example, Dresser rejected an offer to join a cancer trial for her advanced illness because its timeline would have meant a delay in starting treatment.
Jane Reese-Coulbourne, a former cancer trial participant and now consultant, stressed the importance of companies bringing in expert patients for feedback. As a patient advisor, she helped Genentech, a major biotech company responsible for several dozen pioneering drugs, understand why its recruitment for one particular trial was so low: the protocol required enduring four painful bone marrow aspirations, a procedure which extracts fluid from the marrow.
But when collaborating, patient advocacy groups can sometimes find themselves toeing a tricky ethical line between accepting funding from pharmaceutical companies and maintaining their organizational independence.
“Often pharma does bring us in for advice,” McFadyen said, “but sometimes the expectation there is that we’re going to be the people out there making sure [the drug] gets reimbursed.”
Some advocacy groups, he said, will accept payment in exchange for not asking tough questions about access. J. Russell Teagarden, a pharmacist, executive and educator, acknowledged that there are advocacy groups vulnerable to coercion.
“But on the other hand, there are some groups so sophisticated that maybe the companies are vulnerable,” he said, to laughs.
Another source of conflict between companies and patients is rhetoric. Too often, companies employ hyperbolic language like “breakthrough” to attract investors, while desperate patients line up for trials that haven’t in actuality even begun.
Bateman-House said that the lack of scientific literacy in the general population, who are prone to believing the science holds all the answers, is a major source of confusion. In fact the vast majority of drugs fail in the lab long before the point of human trials. Indeed, only one in a thousand compounds graduates to clinical testing, and of those, only about 10 percent eventually cross the finish line.
Issues about trial demographics came to the fore during a vibrant Q&A. One audience member expressed concern over how to expand clinical trials to underrepresented groups, like pediatric cancer patients. McFadyen suggested that is possible if parents push for it. Another spoke of disappointment over the fact that only 10 percent of patients qualify for trials. Several panelists responded that legislation is underway in the Senate to expand inclusion criteria so more people can participate in research.
Expert Opinion Pharmacotherapy 16(9):1275-9, Jun 2015.
Modern Trends in Clinical Drug Development
Speakers
Janet Woodcock U.S. Food and Drug Administration
Audience Q&A with Janet Woodcock
Highlights
Clinical trials are a prohibitively expensive element of drug development.
Trial designs, no matter how novel, will only be as good as the knowledge underlying them.
Randomization remains an important tool but is not always necessary in novel designs.
The system requires reform to incentivize continuous, collaborative platform trials.
Designing alternatives
The clinical trial system in the United States is broken because it isn’t “fit for purpose,” argued Janet Woodcock, director of the Center for Drug Evaluation and Research at the FDA. Because trials are so expensive and time-consuming, many questions remain unanswered after a drug is approved, leading to health care practices that too often lack high-quality evidence.
She discussed the wasteful efforts when a sponsor sets up a trial, tests an intervention, and then walks away because either the trial fails or the drug reaches the market. Instead, the future ought to bring more continuous, ongoing platform trials that can answer multiple questions at once, with data shared among health care networks.
“The goal,” she said, “is not to test a specific therapy, but to bring about continuous improvement in disease outcomes.”
In the current era, rapidly evolving science is driving novel research designs. Molecularly targeted therapies are on the rise, along with drugs that are “disease agnostic,” such as those that might target a specific biomarker appearing across tumor types, for example. With rare, life-threatening diseases that lack treatment options, she suggested it may in fact be adequate to test a targeted therapy, which is expected to show a large treatment effect, in a single-arm trial with an extended phase one cohort.
“I’m going to say something heretical, but oncology has been doing this, and it’s perfectly reasonable in my mind under these circumstances,” she said.
While a very useful tool, randomization in her mind is not an imperative. However, “it’s foolish not to use it if at all possible,” she added, such as if the disease outcomes are very variable or researchers don’t expect to get a homerun treatment effect.
But as more development programs are working on very rare and orphan diseases, the FDA is approving drugs based on limited trials that may lack randomization, as with an antidote for methotrexate toxicity devised from the data of 22 patients. Such cases involve a serious unmet medical need, a well-understood disease, highly plausible biomarkers that can be easily measured in a standardized way, and a drug that yields a large treatment effect.
She cautioned, however, that the design of a trial is only as good as the quality of the knowledge underlying it. Biomarkers may mistakenly drive a development program, for example, if they are not reproducibly measured, accurate, or predictive. Before starting trials in humans, researchers should be confident that a biomarker is “reasonably likely to predict clinical benefit,” she said, suggesting that randomization usually remains the best design in this situation.
Calling for greater efficiency overall, she urged a shift toward collaborative platform trials that integrate research and practice. But implementing changes to the status quo poses a serious challenge.
“In this translational world of continuous improvement in medicine, nobody is charged to do it and that’s the real problem,” she acknowledged. Since there isn’t a key stakeholder, she urged patients to rise up and demand reform.
Lessons from the Eteplirsen Drug Trial for Duchenne Muscular Dystrophy
Speakers
Pat Furlong, Panelist Parent Project Muscular Distrophy
Edward M. Kaye, Panelist Sarepta Therapeutics
Ellis Frank Unger, Panelist U.S. Food and Drug Administration
David Scheer, Panelist Scheer & Company, Inc.
Meg Tirrell, Moderator CNBC
Panel Discussion Lessons from the Eteplirsen Drug Trial for Duchenne Muscular Dystrophy
Highlights
Patients-researcher collaboration could enhance planning of clinical trials.
Surrogate endpoints should comport with clinical gains.
Understanding a disease’s natural history and its biomarkers is crucial to guiding high-quality research.
Limited trials can lead to accelerated approvals, but questions may remain about real-world effectiveness and who will pay for the drug.
Case study
The accelerated FDA approval late last year of the drug Eteplirsen for Duchenne Muscular Dystrophy (a disorder that predominantly manifests in young boys and progresses rapidly) based on controversial data from a 12-patient randomized trial, set off a lively discussion. Sufferers with this rare disease progressively lose muscle function and previously had no treatment options before Eteplirsen came on the market in late 2016, gaining approval even though its effectiveness is still being debated. Moderator Meg Tirrell of CNBC opened by asking the panelists whether the case established any precedents.
Ellis Unger, director of Drug Evaluation-I in the Office of New Drugs at the FDA, offered his concern about the trial’s surrogate endpoint: the drug was approved based on a small increase in the amount of dystrophin, a key protein, found in skeletal muscle. However, whether the increase yields meaningful clinical benefits remains an open question and a flash point for controversy. Unger said he worried that the case will prompt other companies to present similarly limited data and expect to gain FDA approval.
But Pat Furlong, a patient activist and the mother of two boys who died of the disease, argued that the drug did show improvement in the gaits of those who took it, and that desperate patients should not be prevented from taking risks. “It has rocked my world,” she said, speaking of the hope it’s brought to patients who now have the option to try a drug where before none existed.
Edward Kaye, CEO of Sarepta Therapeutics, the drug’s sponsor, contended that small amounts of a biologically active component can work, and said that “the bigger precedent is patient involvement.” Throughout the study, his company worked with patients’ families to understand what quality-of-life outcomes would be most meaningful from a drug, such as the ability to go to the bathroom independently. He also collaborated with other companies to accelerate the search for biomarkers. Their collective pact to publish joint findings represents a notable shift in how research is done.
“It’s not one company against another,” he said, “it’s a number of companies and patient groups against the disease.”
In response to a question about the importance of biomarkers in raising capital for research, David Scheer, an entrepreneur in the life sciences, said that they provide crucial preclinical data.
“Without having some sort of biomarker technology that can facilitate translational medicine, we might be shooting in the blind,” he explained.
The discussion turned heated when Unger described the unusual public comment period during an FDA advisory meeting prior to the drug’s approval. While some of the boys from the trial declared their improvement, Unger said the data showed they were in fact deteriorating. He also described the comment period as “a circus,” because in his view patients and families went over the line, taking too long, and in some instances heckling the committee.
Shortly thereafter, patient advocate Andrew McFadyen approached the microphone and admonished Unger. McFadyen told him to show more respect for families with dying children and to listen to their stories for a year if necessary. “If you can’t do that, you should give your chair up to someone else,” he declared.
While Unger apologized for using the word “circus,” he defended his remarks, recounting the conduct of the session.
“When the deputy director of the Neurology Division told a very personal story of tragedy, he was heckled.” He continued, “we have to draw a line somewhere, and we thought that the time we allotted was reasonable… the catcalls, and the heckling, it was very disheartening.”
Former FDA commissioner Robert Califf stepped up to offer additional insight into the process. “Advisory committees are so named because they do not make the decisions,” Califf said. “Full time government employees are the ones who make the decisions and most people are still confused by that.”
“There was no one in the FDA who thought that the studies were well done,” he added. “I don’t think these decisions would have been so hard otherwise.”
Another audience question addressed the cost of the drug: At a price of $300,000 annually per patient, insurers are balking; they want to see real-life evidence of effectiveness before paying for it. Kaye’s company has started a registry to gather such data, but he said that new therapies in small populations entail expensive drugs because limited numbers of patients receive them.
“So, the cost of developing the drug is transferred to them,” he said. “That is the cost of innovation.”
George D. Demetri, Panelist Dana-Farber Cancer Institute
Anne Cropp, Panelist Early Access Care, LLC
Christopher Robertson, Panelist University of Arizona
John (L.P.) Thompson, Panelist Columbia University
Donald Berry, Moderator MD Anderson Cancer Center
Panel Discussion A Way Forward
Highlights
Platform trials are a key way to merge research and practice.
RCTs are still considered the definitive trial design for reducing bias.
Sharing well-established trial templates for common diseases will eliminate redundant efforts.
Sponsors should make compliance less burdensome for patients.
Refinements or reinvention?
The lively panelists in the afternoon session had no qualms about offering blunt criticism of the status quo. Echoing a theme of the conference, moderator Donald Berry, a statistician at MD Anderson Cancer Center, underscored the need to merge research with practice.
“It’s inevitable,” he said. “We have to figure out how to do it, and platform trials may be the way.”
George Demetri, a medical oncologist at the Dana-Farber Cancer Institute, summed up the situation more derisively: “The clinical trial system is broken,” he said, “and we’re not being honest with the public about what we do and don’t know.” He argued that the benefits of precision medicine and testing for mutations are oversold to patients, particularly by academic institutions.
Christopher Robertson, a law professor at the University of Arizona, raised concerns about bias skewing results, especially in cancer drugs with small effect sizes. Blinding not only patients, but also investigators and statisticians, is crucial to finding legitimate outcomes. Another way to reduce bias is to specify endpoints before the start of a trial to avoid coming up with erroneous probability values, he said.
Anne Cropp, chief scientific officer of Early Access Care, suggested that one way to improve efficiency in the development of new protocols is to make data from the NIH more widely available so that companies working on common diseases like Alzheimer’s and diabetes can use established trial templates, with well-defined endpoints, rather than starting from scratch. She also urged physicians to become more literate in drug testing, citing a Tufts study that revealed a surprising lack of knowledge among doctors regarding the ins and outs of clinical trials.
John Thompson, a professor of biostatistics and neurology at Columbia, cautioned against a premature rejection of double-blind, placebo-controlled RCTs. He worked on just such a trial involving a treatment for ALS, despite being told it was impossible because patients would decline to participate.
“Must RCTs give way?” he asked. “A flexible no, although many people will hear it as a yes, because I envisage considerable fast-moving changes.…It’s a matter of adding to and expanding rather than abandoning the existing techniques.”
A key to the ALS trial’s success, he said, was explaining to patients the importance of its design to gain their trust and cooperation. To help with recruitment, he suggested that disease advocacy groups post the details of ongoing trials on their websites, after networking with investigators, so that patients can find the information and take it to their doctors.
During the audience comment period, Ellis Unger of the FDA offered additional suggestions. He mentioned a “very powerful” trial design that he believes is not used enough: randomized withdrawal, in which responders stop taking a drug and investigators observe what happens. He also urged sponsors to make compliance easier for patients by letting them participate from home, via Skype, when possible, and to limit the number of scans and tests they must undergo.
“The FDA does not need forty thousand blood tests or four X-rays per person to approve a drug,” he said dryly.
Panel Discussion
Further Readings
Journal Articles
Poor Physician and Nurse Engagement Contributes to Low Patient Recruitment Rates
Tufts Center for the Study of Drug Development, Jan 2017.
Nature Reviews Clinical Oncology 9(4):199-207, Nov 2011.
Ethics Panel Wrap-up
What is the Future of Accelerated Development and the Randomized Controlled Trial Standards?
Speakers
Nancy King, Panelist Wake Forest School of Medicine
Vinay Prasad, Panelist Oregon Health and Science University
Eric H. Rubin, Panelist Merck & Co., Inc.
Jeffrey S. Weber, Panelist NYU Langone Medical Center
Timothy Caulfield, Moderator University of Alberta
Panel Discussion Ethics Panel Wrap-up
Highlights
RCTs remain a key method for overcoming bias and threats to validity.
But not every drug requires a large, expensive RCT for initial approval.
Platform trials retain randomization while operating more efficiently.
The system requires reform to incentivize collaboration and transparency.
One tool along the continuum
The final presenters agreed that RCTs are not going away anytime soon, but there are changes in how and when they are being used.
Vinay Prasad, a hematologist-oncologist at Oregon Health and Sciences University, defended the RCT against common criticisms. If such trials don’t reflect real-world populations, he said that is due to strict inclusion criteria, not the design. And if endpoints don’t represent clinical outcomes, the RCT itself is not to blame. That would be “like blaming the Wright brothers for United Airlines,” he quipped.
Eric Rubin, vice president of oncology clinical research at Merck, argued that the title of the conference should not be, “Must RCTs give way?” but rather, “Should RCTs not get in the way?” For example, a single-arm study in a drug with a large effect size can lead to initial approval faster than a standard RCT. Finding such a drug requires high-quality basic research and reproducible preclinical studies, he added.
Jeffrey Weber, deputy director of the Perlmutter Cancer Center at NYU, acknowledged that everyone “worships the god of the randomized, phase three trial,” but he expressed concern over its exploding costs and suggested that modifications in some cases could be appropriate. He proposed using more novel endpoints, such as landmark survival at one and two years, combined with a quality-of-life questionnaire.
“In the immunotherapy era,” he said, “I think we can afford to be more flexible than to do an RCT with a thousand participants and the only endpoint is survival.”
But Prasad was quick with a rebuttal, arguing that progression-free survival is based on an arbitrary line in the sand and is not necessarily correlated to eventual survival.
Rubin agreed with Weber that RCTs are the definitive way to demonstrate benefit, but that at least in oncology, an RCT with overall survival as the endpoint is not required to approve a drug. Rubin suggested that it is possible to deliver promising therapies quickly, without sacrificing randomization, by conducting early phase explanatory trials for initial registration and then a post-market RCT to verify early results.
For example, at Merck he led the development of a melanoma drug that was approved after a single-arm study in patients with advanced illness who were out of options. Afterward, Merck followed up with a randomized trial in less sick patients to compare the new drug against existing alternatives, in which case researchers still retained equipoise. This scenario shows it’s possible to do both—accelerate approval, in this case by three years, and still conduct a confirmatory RCT.
Rubin reiterated an idea that got a lot of play across the conference—the notion that a collaborative platform trials could streamline the process of matching drugs to patients across a spectrum of disease, as was the case in I-SPY2. Such trials benefit patients by letting them get assigned to one arm no matter their cancer.
But Nancy King, a professor of social sciences and health policy at Wake Forest, pointed out that academic institutions and businesses aren’t structured to reward transparency and collaboration over competition.
“You have to be able to turn the battleship,” she remarked.
In a discussion on the exorbitant expense of running trials, Weber said that the regulatory scrutiny has proliferated over the last decade, adding to the cost burden.
“We have monitors that monitor the monitors,” he joked.
Ultimately, even as some areas of drug development move away from the RCT, it remains a fundamental tool along a continuum of designs. One reason it may never vanish is that it can act as a bulwark against the fallibility of human nature.
“Our capacity for hope makes us incredibly susceptible to inferior levels of evidence,” Prasad reflected.
In his opinion, the beauty of randomization is that with a modest effect size, there is no better way to tease apart what works.
Journal of Clinical Epidemiology 66(4):361-366, April 2013.
Open Questions
How can researchers and industry sponsors be incentivized to collaborate on platform trials and sharing data?
How can researchers accelerate drug development without sacrificing the collection of data on efficacy and safety?
How can society increase scientific literacy among the public to encourage participation in research, rather than view it as inherently risky?
How can the medical profession systematically integrate research and clinical practice?
If a drug is granted accelerated approval after a single-arm trial, how can the sponsor be held accountable for collecting post-market data on safety and efficacy?
Will insurers pay for drugs that are approved based on limited or non-randomized trials?
During the next humanitarian emergency, is it feasible and ethical to test interventions with a RCT?
How can costs be better managed to complete a RCT without the prohibitive expenses?
Can decreasing the amount of oversight streamline trials without sacrificing protection for research participants?
Can sponsors and patients work together to design trials at the earliest stages, ensuring that compliance in a protocol is not overly burdensome?
Should a standard RCT remain the default design?
Is choosing between a RCT and an alternative design a false dichotomy?
How can trials better accommodate broad patient populations to yield real-world data and integrate more patients into research?
Who should decide how much risk is appropriate in trying an unproven therapy?
Will big data solve quandaries of speed and the historical limits on the RCT?
Should rare diseases with limited numbers of patients available for trials have a lower evidentiary standard for drug approval?
What can be done to reign in exorbitant drug prices?
Will automation and electronic medical records help motivate doctors to participate in large-scale practical trials?
How can society implement the changes required to modernize the clinical trial enterprise?
Vijay Sankaran, MD, PhD, discusses recent developments in the treatment of sickle cell disease and other blood disorders, with a specific focus on gene targeting.
Published August 16, 2017
By Marie Gentile and Robert Birchard
Microscopic view of sicke cells causing anemia disease.
In 1973 the lifespan of a person with sickle cell disease (SCD) in the United States was 14 years. Today, the lifespan of a person with SCD has increased to 40-60 years. While diagnosis and care for people with SCD has improved, treatment options remain limited. In fact, before the recent approval of Endari there was only one FDA approved treatment for SCD, an inherited red blood cell disorder where red blood cells become rigid and sickle shaped impeding the flow of blood and oxygen through the body’s blood vessels.
Still, insights into the pathophysiology of SCD and other blood disorders has led to promising new treatment approaches. At the forefront of this research is Dr. Vijay Sankaran an Assistant Professor of Pediatrics at Harvard Medical School and Attending Physician in Hematology/Oncology at Boston Children’s Hospital and the Dana-Farber Cancer Institute.
Dr. Sankaran’s research into inherited blood disorders was inspired by his initial work in understanding the mechanisms behind fetal hemoglobin regulation. During gestation the fetus expresses a form of hemoglobin that helps extract oxygen from the mother. After birth this mechanism is silenced and fetal hemoglobin is no longer produced. People with SCD could benefit greatly from the continued production of the fetal form of hemoglobin.
Research on the SH2B3 Gene
“We knew that patients with a number of inherited blood disorders such as SCD and beta-thalassemia can actually do much better if they have higher levels of fetal hemoglobin. There were clear indications that inducing fetal hemoglobin could be effective, but we lacked the tools to reactivate fetal hemoglobin in adults,” he explained. This line of research eventually led Dr. Sankaran to identify and demonstrate that the BCL11A gene is a potential therapeutic target. BCL11A could be induced to produce fetal hemoglobin, which would produce healthier red blood cells and fewer sickled cells.
Related to Dr. Sankaran’s research into activating the BCL11A gene in adults is his research into the regulation of blood production more generally. For example, work from his group has shown that shutting down the SH2B3 gene which, “normally functions as a break on red blood cell production,” could be valuable for, “applications where people are interested in trying to produce blood cells outside of the body for transfusion or other purposes.”
If the SH2B3 gene “break” was removed more healthy red blood cells could be produced. This is tremendously important for people with SCD because, “Many of them cannot tolerate the blood from most donors, because they have developed antibodies against the donor’s blood antigens.” His research on the SH2B3 gene could lead to less expensive and more widely available methods for manufacturing red blood cells.
Take Risks and Find Multiple Mentors
Dr. Vijay Sankaran
The cost and time associated with the research and development of new treatments is immense and the length of the development pipeline represents a significant clinical challenge. As an example, Dr. Sankaran noted how the development of Endari began three to four decades ago. But, he believes these challenges can be overcome, “Using insights from human genetics and natural observation, can help in the development of new treatments for SCD. For many years it was unclear what clinical endpoints would be ideal to go after in SCD. There are many manifestations, but the more candidate therapeutics we identify, and the more clinical trials we perform, we can better learn how to measure the effect of these endpoints.”
Finally Dr. Sankaran offered some advice to future researchers, “I think the key is to not be afraid to take risks. It’s critical to find not just a single mentor, but many mentors to help shape your career. Find and talk to a number of mentors who can help guide you. Sometimes it’s very easy to lose focus in an area. I was very lucky as a graduate student to work with Stuart Orkin, who allowed me to take some risks and pursue research into fetal hemoglobin,” he said.
“I then continued this research as a post-doctoral fellow with Eric Lander at the Broad Institute and Harvey Lodish at the Whitehead Institute, while David Nathan and Sam Lux – among others – at Boston Children’s have helped me to develop as a clinician as well to make sure the work we pursue in the lab relates to the patients I care for.”
Two publications from The New York Academy of Sciences examine pre-approval access to investigational drugs from a range of stakeholders and perspectives.
Under expanded access (also called compassionate use), patients who suffer from serious or immediately life-threatening diseases for whom no comparable or satisfactory alternative therapy is available can access drugs and medical devices that are not approved by the FDA and are currently being tested in clinical trials. A total of 29 states have also passed “right-to-try” laws allowing terminally ill patients to access experimental therapies, but there are many questions about the safety and efficacy of such treatments that are not FDA-approved.
Recently the FDA announced significant changes to shorten and simplify the application process used by physicians to request expanded access to investigational drugs for individual patients. Some are predicting that the FDA may not approve a drug to treat Duchenne muscular dystrophy that is currently under review, but will allow compassionate use while additional studies are conducted.
Regardless of the FDA decision, the debate over compassionate use will continue and evolve as additional treatments are brought to the forefront of experimental medicine and research.
June 2, 2016 Patients with life-threatening illnesses face challenges in accessing potential therapies at the cutting-edge of R&D which have not yet been proven in a clinical trial. This podcast will explore the provocative and emotional stories of patients, family members, advocates, researchers, physicians, and the regulators charged with keeping medicines in the marketplace safe and effective.
Biotechnology and nanotechnology have given rise to a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there also exist non-biological complex drug products (NBCDs), including many nanomedicines such as iron-carbohydrate complexes, several drug carrying liposomes or emulsions, and glatiramoids. These products are difficult to characterize—often the key features for efficacy and safety are not well understood. These factors pose unique challenges for pharmaceutical companies and regulatory agencies when comparing generic complex drugs to their branded counterparts.
On November 9, 2016, representatives from academia, industry, and regulatory agencies convened at the New York Academy of Sciences for the symposium Equivalence of Complex Drug Products: Scientific and Regulatory Challenges, an opportunity to discuss how to approach complex generics. Regulatory officials described how agencies approach evaluating complex generics for marketing approval, while industry speakers presented several examples that demonstrate the difficulties in characterizing complex drugs.
The symposium was presented by the Non Biological Complex Drugs Working Group, the Nanotechnology Characterization Laboratory, and the New York Academy of Sciences.
Lawrence Mayer, senior vice president of discovery at Jazz Pharmaceuticals, has played a lead role in the discovery and development of a number of oncology drugs, several of which eventually achieved market approval. He has also held senior management positions at The Canadian Liposome Company and QLT, Inc. before joining the British Columbia (BC) Cancer Agency, where he established and directed the Health Canada-accredited Investigational Drug Program. Celator Pharmaceuticals, now a subsidiary of Jazz Pharmaceuticals, was formed in 2000 as a spin-out of Mayer’s laboratory at the BC Cancer Agency. Mayer has authored more than 250 scientific publications and has more than 35 patent families awarded or pending. Mayer received his BS in both chemistry and biology, summa cum laude, from Wartburg College and his PhD in biochemistry from the University of Minnesota.
Daan Crommelin is professor emeritus at the Department of Pharmaceutics at Utrecht University. Until December 2011 he was scientific director of the Dutch Top Institute Pharma in Leiden. He is adjunct professor at the Department of Pharmaceutics and Pharmaceutical Chemistry at the University of Utah. Crommelin is co-founder of OctoPlus, a Leiden based company specialized in the development of pharmaceutical (mainly protein based) product formulations and advanced drug delivery systems. He published extensively and is on the editorial board of 10 peer reviewed journals in the pharmaceutical sciences. He is Editor-in-Chief of the AAPS book series Advances in the Pharmaceutical Sciences. He advises venture capital groups and acts as consultant. He chairs the UCAB Foundation: the Utrecht Center of Excellence for Affordable Biotherapeutics, a WHO supported initiative. He chaired the Board of Pharmaceutical Sciences of the International Pharmaceutical Federation (F.I.P.), was chair of the organizing committee of the Pharmaceutical Sciences World Conference 2007 in Amsterdam. He is past president of the European Federation of Pharmaceutical Sciences (EUFEPS) and past vice-chair of the scientific advisory board of the European Innovative Medicines Initiative (IMI).
A pharmacist by training, Beat Flühmann holds a PhD in molecular biology. In his current position Flühmann serves as global lead on non-biological complex drugs at Vifor Pharma Ltd Switzerland, with a main interest in regulatory aspects of nanomedicines. Previously, Flühmann led a global multidisciplinary research and development team at Roche/DSM nutritional products developing novel compounds for the prevention and treatment of diabetes. He also is a steering committee member of the Non-Biological Complex Drugs Working Group hosted at the nonprofit Lygature, a group set up to discuss science-based approval and post-approval standards to ensure patient safety and benefit with non-biological complex drugs. The working group engages in activities to publish and discus scientific evidence with authorities, experts, health care providers, and is involved in scientific education and training to relevant stakeholders. Flühmann also sits on the advisory board of the GoNanoBioMat project, a multinational research project in the field of nanomedicine.
Joseph L. Glajch is director of analytical development at Momenta Pharmaceuticals. He received his AB in chemistry at Cornell University and PhD in analytical chemistry at the University of Georgia under L.B. (Buck) Rogers. He has held technical and R&D management positions at DuPont, Bristol-Myers Squibb, Certus, and Momenta, with an emphasis on HPLC column and method development and pharmaceutical development and analysis. He has served as president and program chairman of the Analytical Division of the American Chemical Society and the Chromatography Forum of the Delaware Valley, as well as program chair of the Gordon Conference on Analytical Chemistry. He has served on the editorial advisory boards of Analytical Chemistry, the Journal of Chromatography, and LC/GC. He is a member of the USP Expert Committee on General Chemical Analysis and has over 40 publications, is co-author of three books, and holds six patents on HPLC column materials and medical imaging agents.
Elwyn Griffiths, PhD, DSc
World Health Organization and Health Canada publications
Elwyn Griffiths is currently a consultant in vaccines and biotherapeutics to WHO and a member of the WHO Expert Committee on Biological Standardization. He is also a member of the Clinical Trials, Biologicals and Vaccines Expert Advisory Group of the UK Commission on Human Medicines and of the Expert Advisory Group on Biological and Biotechnology products of the British Pharmacopoeia Commission.
In 2011, Griffiths retired as director general, biologics and genetic therapies directorate of Health Canada, an organization he joined in 2003 upon retirement from the World Health Organization. Griffthis holds a PhD and a DSc degree from the University of Wales. In 1980, he became a senior member of staff at the UK National Institute for Biological Standards and Control, and in 1994 was appointed chief of biologicals at WHO. From 1994 until the end of 2002, Griffiths was responsible for WHO’s program for providing international written and physical standards for vaccines, blood products and biotherapeutics.
Iris Grossman, VP, global head of the Personalized & Predictive Medicine (PPM) and Big Data Analytics unit for Teva Global R&D, is currently charged with defining and implementing Teva’s global PMP strategy, covering both discovery and development R&D programs. Israel’s leading financial magazine, Globes Magazine, selected Grossman as one of the country’s top 40 professionals under 40 years of age in 2013.
Prior to joining Teva, Grossman was CEO and president of the pharmacogenetics management consultancy IsraGene Ltd.. This followed several years of spearheading pipeline pharmacogenetic programs for industry and academia as director of pharmacogenetics at Cabernet Pharmaceuticals Inc. Grossman moved into consultancy having been responsible for running large-scale pharmacogenetic programs at GlaxoSmithKline, with an emphasis on infectious and neurological diseases.
Grossman received her PhD from the Technion–Israel Institute of Technology, where her research project, conducted in collaboration with the Weizmann Institute for Science, investigated pharmacogenetic markers of multiple sclerosis treatment response.
Wenlei Jiang, PhD
Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration website | publications
Wenlei Jiang is currently a senior science advisor in the Office of Research and Standards (ORS)/Office of Generic Drugs (OGD)/Center for Drug Evaluation and Research (CDER). She is mainly responsible for coordinating post-market generic drug safety investigation, representing ORS on OGD’s new international harmonization activities, and developing opportunities for scientific outreach. Previously, she served as the acting deputy director of ORS, where she provided oversight on Generic Drug User Fee Act (GDUFA) regulatory science research programs. She used to work in the Division of Chemistry, OGD to review the chemistry and manufacturing control (CMC) sections of ANDAs. Prior to joining FDA, she was at Novartis Pharmaceutical Corporation where her responsibilities included formulation development of conventional liquid and solid dosage forms, as well as advanced parenteral drug delivery systems. She received her PhD in pharmaceutics and pharmaceutical chemistry from Ohio State University in 2001.
Scott McNeil serves as director of the Nanotechnology Characterization Laboratory (NCL) for Leidos Biomedical Research and Frederick National Laboratory for Cancer Research, where he coordinates preclinical characterization of nanotech cancer therapeutics and diagnostics. At the NCL, McNeil leads a team of scientists responsible for testing candidate nanotech drugs and diagnostics, evaluating safety and efficacy, and assisting with product development. McNeil is a member of several working groups on nanomedicine, environmental health and safety, and other nanotechnology issues. He is an invited speaker to numerous nanotechnology-related conferences and has several patents pending related to nanotechnology and biotechnology. He is also a vice president at Leidos Biomedical Research.
McNeil’s professional career includes tenure as an Army officer, with tours as chief of biochemistry at Tripler Army Medical Center, and as a combat arms officer during the Gulf War. He received his bachelor’s degree in chemistry from Portland State University and his doctorate in cell biology from Oregon Health Sciences University.
Kouros Motamed, PhD has been the Director of Drug Development at NantBioScience, Inc. since April 2016. Prior to that, he has served as VP of Strategic Alliances and Clinical Communications and VP of Clinical Development and Nanomedicine at Sorrento Therapeutics from 2013 to 2016. He has also served as a co-founder and CSO/CTO of Igdrasol, Inc. and Biomiga Diagnostics start-up companies from 2011–2013. Dr. Motamed has also served as the MOA and Molecular Biology Group Head at Celgene Corp. and Abraxis BioScience Inc. from 2007–2011. Dr. Motamed held an Assistant Professorship position in the Department of Pathology and Vascular Biology Center at Georgia Health Sciences University from 2002–2007. He has over 30 original publications in peer-reviewed journals, over 50 conference presentations and has 5 issued patents. He has served on the Editorial Board of Journal of Nanomaterials & Molecular Nanotechnology since 2013. Dr. Motamed received a BS degree in Biology from University of San Francisco and a PhD degree from the University of California, Davis in Microbiology.
Stefan Mühlebach, regulatory science lead for non-biological complex drugs at Vifor Pharma–Fresenius Medical Care Renal Pharma Ltd. (Switzerland), chairs the Non-Biological Complex Drugs (NBCDs) Working Group at Lygature, a nonprofit, private-public partnership in the Netherlands. He is a university professor, medical faculty member, and member of the clinical pharmacy & epidemiology unit at the Department of Pharmaceutical Sciences at the Natural Sciences Faculty (Switzerland). Research activities, graduate and postgraduate teaching cover topics in pharmacology, clinical nutrition, hospital pharmacy, and regulatory sciences. He has authored over 100 peer-reviewed papers and several book chapters. From 1980 to 2005, he served as a chief hospital pharmacist in Switzerland. He is an honorary member of the Swiss Association of Public Health Administration and Hospital Pharmacists and a board member of the Swiss Academy of Pharmaceutical Sciences. In 2008, he joined Vifor Pharma Ltd as chief scientific officer.
Chetan Pujara is vice president, small molecule product development at Allergan, Plc. His organization is responsible for designing and developing pharmaceutical dosage forms intended for clinical trials and commercialization. SMPD develops topical sterile ophthalmic solutions, suspensions and emulsions, sustained-release ocular biodegradable implants, oral tablets/capsules, topical dermal gels & creams and other locally acting dosage forms. Prior to joining Allergan, Chetan was employed by Abbott Laboratories/Abbvie, where he held various positions in global pharmaceutical R&D, gaining experience in development of solid oral dosage forms and pediatric oral suspensions.
Pujara is also a member of the USP Dosage Forms Expert Committee and serves on the USP <771> Ophthalmic Preparation Expert Panel. He serves as a scientific advisor to the editors of Journal of Pharmaceutical Sciences and an adjunct professor in the Department of Industrial and Physical Pharmacy, Purdue University. Pujara has also contributed to the Physical Properties Working Group of Product Quality Research Institute.
Andre Raw, PhD
Center for Drug Evaluation and Research, US Food and Drug Administration website | publications
Andre Raw received his BS from the Massachusetts Institute of Technology and his PhD in chemistry from the University of California at Berkeley. He 2001, he joined the FDA as a reviewer within the Office of Generic Drugs, where he is currently acting senior scientific and policy advisor in the Office of Lifecycle Drug Products in the Office of Pharmaceutical Quality. Raw was involved in the development of several FDA initiatives, including the Guidance on Pharmaceutical Solid Polymorphism in Abbreviated New Drug Applications (ANDAs), Regulations on Listing of Polymorph Patents in the “Orange Book,” and Question Based Review – Quality by Design (QbD) Initiative, QbD Example for Generic Modified Release Products, and Guidance for Industry: Pharmaceutical Solid Co-Crystals. He has also been active in addressing scientific and regulatory issues raised in citizen petitions. He was instrumental in FDA’s recent approval of generic versions of complex active ingredients including Lovenox (enoxaparin sodium), and Ferrlecit (sodium ferric gluconate complex in sucrose).
Stephan Stern is acting deputy director and senior principal scientist at the National Cancer Institute’s Nanotechnology Characterization Laboratory (NCL), located at the Frederick National Laboratory for Cancer Research in Frederick, Maryland. NCL assists in all phases of the nanomedicine drug development process, from early preclinical to late stage clinical trials, working with academic laboratories and the pharmaceutical industry. At NCL, Stern oversees nanomedicine pharmacology and toxicology. Stern’s research interests include novel drug formulation, bioanalytical method development, and pharmacokinetic modeling. Prior experience includes a postdoctoral fellowship at the University of North Carolina–Chapel Hill in the Division of Drug Delivery and Disposition, and curriculum in toxicology, and work within regulated areas of the pharmaceutical industry. He received his BS in biochemistry from the University of Rochester and his PhD in toxicology from the University of Connecticut at Storrs. Stern is a diplomate of the American Board of Toxicology.
Wyatt Vreeland, PhD
The National Institute of Standards and Technology publications
Wyatt Vreeland earned his PhD in chemical engineering from Northwestern University, where he developed techniques for the electrophoretic separation of natural and synthetic polymers in microfluidic devices. Later, Vreeland joined National Institute of Standards and Technology as an National Research Council postdoctoral, where Vreeland focused on using liposomes to package chemicals and release those reagents at controlled times and locations in microfluidic systems. Additionally, during his postdoctoral fellowship he undertook the technical development of a field-portable electrophoresis system for forensic DNA analysis for the Department of Justice. Most recently, Vreeland’s research has focused on controlled synthesis and characterization of colloidal protein systems as can be encountered (usually undesirably) in many of today’s complex drug therapeutics. In 2015, Vreeland served as an U.S. State Department Embassy Science Fellow for the U.S. Embassy in Prague, Czech Republic, where he toured the country’s burgeoning biotechnology industry.
Gary West is currently a member of the board of directors of Azaya Therapeutics. A retired radiation oncologist, he graduated from the University of Colorado Medical School and did his radiation oncology residency at the University of New Mexico, where he was affiliated with New Mexico’s Los Alamos Meson Facility (LAMF), before completing his residency at the Joint Center for Radiation Oncology (JCRO), Harvard University. He completed a research fellowship at JCRO, where he investigated chemotherapy drug delivery in human tumor cells. While in the Air Force, he was chief of the radiation oncology department at Wilford Hall USAF Medical Center. He has also served as chief of staff at the University of Texas Health Science Center, Cancer Therapy, and Research Center (CTRC), in San Antonio and as a member of the CTRC board of governors. He is a retired member of the American Society of Clinical Oncologists and the American Society of Therapeutic Radiologists.
Elena Wolff-Holz is medical assessor at the Paul-Ehrlich-Institut and a member of the Biosimilar Working Party (BMWP) of the Committee for Medicinal Products for Human Use (CHMP) and a national expert to the Oncology Working Party (OWP) of the CHMP, where she contributes to scientific advice procedures and the development of guidelines and reflection papers. Wolff-Holz spent 14 years in the biotech industry, where she held various positions in clinical development and medical marketing functions at Centocor Inc (now J&J) and Amgen in the U.S. and in Germany, before joining the German national regulatory agency. In the area of biotherapeutics, she is responsible for advising companies on drug development issues, reviewing applications for marketing authorization in the EU and assessing clinical trial applications. She is also a lecturer covering training of experts and executives from academia, regulatory bodies and biopharmaceutical industry. Wolff-Holz has an MD degree from Heidelberg University and a postdoctoral fellowship at Harvard Medical School.
Gillian Woollett, SVP at Avalere, where she leads the FDA Policy and Regulatory Strategy Practice, an advisory services firm she launched in 2012 that supports clients throughout the healthcare system, from patients to biopharma companies and payers/providers. Woollett and her team translate into practical action all aspects of regulatory engagement strategy and policy development relevant to commercial success for multiple multi-national clients. Concurrently, she created the Avalere FDA Fellows Program to enable scientists to transition effectively into the policy environment with over 20 now having used this stepping stone to transition careers. Woollett earned her BA and MA in biochemistry from the University of Cambridge, and her DPhil in immunology from the University of Oxford. She was a postdoc in the Department of Molecular Biology at the University of Edinburgh, and at the Biomedical Research Institute, Rockville, MD funded by USAID.
Jon de Vlieger, PhD
Non Biological Complex Drugs Working Group and Lygature website | publications
Jon de Vlieger obtained his doctoral degree in bio analytical chemistry from Vrije University (the Netherlands). In 2011, he joined Top Institute Pharma, an independent nonprofit organization based that catalyzes the development of new medical solutions for patients by driving public–private collaboration between academia, industry, and society. Recently, a merger between leading Dutch technology institutes Center for Translational Molecular Medicine and Top Institute Pharma formed Lygature. For Lygature, de Vlieger coordinates several international public private partnerships, including the Non Biological Complex Drugs Working Group, an international network of scientific and clinical experts from academia, industry and regulatory bodies, with expertise in many aspects of the development and evaluation of NBCDs. He is a co-editor of the book on NBCDs in the American Association of Pharmaceutical Scientists’ Advances in the Pharmaceutical Sciences Series.
Organizers
Melanie Brickman Borchard, PhD, MSc The New York Academy of Sciences
Alison Carley, PhD The New York Academy of Sciences
Daan J.A. Crommelin, PhD Utrecht University
Wenlei Jiang, PhD Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration
Scott McNeil, PhD Nanotechnology Characterization Laboratory
Vinod Shah, PhD Non Biological Complex Drugs Working Group
Jon de Vlieger, PhD Lygature
Presented by
How to cite this eBriefing
The New York Academy of Sciences. Equivalence of Complex Drug Products: Scientific and Regulatory Challenges.Academy eBriefings. 2016. Available at: www.nyas.org/ComplexDrugs16-eB
Introduction
Speakers
Jon de Vlieger Non Biological Complex Drugs Working Group
Scott McNeil Lygature and Nanotechnology Characterization Laboratory
According to the Generic Pharmaceutical Association, almost 90% of prescriptions in the United States in 2015 were for generic drugs. Because generics are considered identical to their branded counterparts, pharmaceutical companies can forgo costly large-scale clinical trials. Instead, companies must demonstrate that a generic has pharmaceutical equivalence and bioequivalence to a licensed product. Pharmaceutical equivalence refers to the active ingredient, dosing, and strength, and can be confirmed via chemical and analytical methods. Bioequivalence refers to how a drug acts in the body and is evaluated via pharmacokinetic and/or pharmacodynamic studies. If these two conditions are met, regulatory agencies consider the generic to be safe and efficacious based on the clinical studies conducted on the branded drug.
Demonstrating the equivalence of generic complex drugs to their branded counterpart has unique challenges not encountered with small molecules.
Despite the success and advantages of generic drugs, users of certain drug categories, such as orally inhaled drugs used to treat asthma, currently have no access to generic counterparts. In addition, less than 50% of ophthalmic products and less than 40% of topical drugs have generic versions. That’s largely because these drugs represent complex drug products. In the newly released Generic Drug User Fee Act (GDUFA) “Regulatory Science Pritories,” the FDA defines complex drugs as those having complex active ingredients, such as peptides, polymers, or complex mixtures; complex formulations and/or dosages, such as liposomes, iron colloids, and long-acting injectables; complex routes of delivery, such as locally acting drugs, ophthalmic drugs, suspensions, emulsions, and gels; and/or complex drug–device combinations, such as nasal sprays and inhalers.
Demonstrating the equivalence of generic complex drugs to their branded counterpart has unique challenges not encountered with small molecules. First, the active components of complex drugs are often unknown, as are the critical attributes, i.e., the physical and chemical characteristics essential for efficacy and safety. Complex drugs are also difficult to fully characterize, and the products are very sensitive to changes in manufacturing, which is often proprietary.
In addition to above mentioned complex drug categories, the symposium also addressed biosimilars, generic versions of biologics, such as monoclonal antibodies, which share several of the hurdles to demonstrating equivalence.
Drugs can be classified into three categories. Small molecules are easy to characterize and to demonstrate equivalence. Biologics and complex drugs are more complicated, and it is difficult to demonstrate equivalence. (Image courtesy of Stefan Mühlebach)
Lawrence Mayer of Jazz Pharmaceuticals gave the keynote address on the development of a liposome-based drug delivery vehicle designed to maintain optimal levels of two cytostatics.
Several speakers spoke about the regulatory issues for biosimilars and complex drugs. Daan Crommelin of Utrecht University and Gillian Woollett of Avalere Health outlined some of the general issues to regulating generic complex drugs. Wenlei Jiang of the US Food and Drug Administration (FDA) and Elena Wolff-Holz of the Paul Ehrlich Institute provided the perspectives of the FDA and European Medicines Agency (EMA), respectively. Elywn Griffiths of the World Health Organization (WHO) outlined the WHO’s perspective.
There were several presentations on the approval of Glatopa (glatiramer acetate injection), a generic version of Copaxone (glatiramer acetate injection) for the treatment of multiple sclerosis. Andre Raw of the FDA outlined the evidence that the FDA required for approval of Glatopa while Joseph Glajch of Momenta Pharmaceuticals described the company’s approach to developing and characterizing it. Iris Grossman of Teva Pharmaceuticals presented data that show differences between the brand name drug and its generic counterpart.
Several generic versions of iron sucrose have been approved throughout the world. Stefan Mühlebach of Vifor Pharma presented evidence that several iron sucrose similars (ISS) are less effective than their branded counterparts. Beat Flühmann, also of Vifor, discussed his work on understanding pharmacists’ perspective on ISS.
Three speakers presented their approaches to evaluating the equivalence of complex drugs. Chetan Pujara of Allergan presented data on analyzing the equivalence of ophthalmic emulsions. Gary West of Azaya Therapeutics discussed regulatory hurdles to developing a generic form of Doxil (doxorubicin HCl liposome injection). Kouros Motamed of NantBioScience discussed the company’s efforts to develop a new drug delivery method for the cytostatic paclitaxel.
Two speakers focused on technical challenges to characterizing complex drugs. Wyatt Vreeland of the National Institute of Standards and Technology (NIST) described the advantages and caveats of several techniques to measure nanoparticle size. Stephan Stern of the Nanotechnology Characterization Laboratory (NCL) described a new technique to more accurately measure nanomedicines in the blood.
Speaker Presentation
Keynote Presentation
Keynote Speaker
Lawrence Mayer Jazz Pharmaceuticals
Highlights
Drug-delivery vehicles can control the pharmacokinetics of drug combinations to maintain a drug ratio that maximizes efficacy while minimizing toxicity.
Vyxeos, a nanoscale drug delivery system, was developed to deliver two chemotherapies, daunorubicin and cytarabine, in a 5-to-1 molar ratio.
In Phase 3 trials, Vyxeos demonstrated improved overall survival compared to daunorubicin plus cytarabine in patients with acute myeloid leukemia.
Built to scale
Lawrence Mayer described the development of Vyxeos (formerly CPX-351), a drug delivery system in Phase 3 trials for the treatment of acute myeloid leukemia (AML).
Vyxeos is a liposome-based drug delivery system that delivers the chemotherapies daunorubicin and cytarabine in a 5-to-1 ratio. In various cancer cell lines, this ratio was shown to have either additive or synergistic efficacy. Mayer described several of the technical features that can be altered to achieve the desired drug release rate, including membrane rigidity, charge, cholesterol content, and copper content.
The relative ratios of the chemotherapies cytarabine and daunorubicin can affect the combination’s efficacy. Some ratios are synergistic, while others are additive or antagonistic. (Image courtesy of Lawrence Mayer)
Vyxeos was compared to the current chemotherapy regimen of cytarabine and daunorubicin in two Phase 2 and one Phase 3 clinical studies in patients with AML. In all three trials, patients treated with Vyxeos had a significantly higher overall survival. Other indicators of efficacy, such as response rates and post-transplant survival were also better in patients treated with Vyxeos. Jazz Pharmaceuticals is pursuing FDA approval of Vyxeos. The FDA granted the drug breakthrough status earlier this year.
Mayer stressed the importance of a scalable manufacturing process and biophysical characterization early in drug development. A well-characterized biophysical profile ensures that the product produced in large-scale production is the same as that produced and studied during small-scale testing. It also ensures that the features of the product do not vary considerably from batch to batch.
Speaker Presentation
Video Chapters 00:00 Introduction 06:00 Key to exploiting drug ratio-dependent synergy 12:34 Leukemia cell update of intact liposomes 19:18 A robust commercial-scale nanomedicine 27:00 Conclusions
Regulatory Considerations
Speakers
Daan J.A. Crommelin, PhD Utrecht University
Elwyn Griffiths World Health Organization and Health Canada
Wenlei Jiang, PhD Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration
Elena Wolff-Holz Paul Ehrlich Institute
Gillian Woollett Avalere Health
Panel Discussion Moderator:
Scott McNeil Nanotechnology Characterization Laboratory
Highlights
Regulatory pathways for small molecule generics and biosimilars are well established, while requirements for non-biologic complex drugs are considered on a case-by-case basis.
The FDA is continually investigating new pharmacokinetic data and methods to assess the bioequivalence of complex drugs.
New guidance was released by the EMA in 2014 that expands the definition of biosimilar and provides additional direction to industry.
Regulatory pathways for generics and biosimilars
Daan Crommelin began by defining some key terms relating to complex drug products and outlining the regulatory pathways for different types of drugs. According to Crommelin, drugs can be divided into three main categories: small molecules; biologics, such as vaccines, blood and blood components, gene therapies, tissues, and recombinant proteins; and non-biologic complex drugs (NBCDs), synthetic drugs that do not have a single, homogeneous active substance and cannot be fully characterized. The composition, quality and in vivo performance of NBCDs are highly dependent on the manufacturing processes of the active ingredient as well as (in most cases) the formulation. They often consist of nanomedicines such as polymeric micelles, liposomes, or peptide-polymers. Crommelin pointed out that regulatory agencies do not always agree on these definitions; while the EMA considers low molecular weight heparin a biologic, the FDA considers it a complex drug.
The regulatory pathways for small molecules and biologics are relatively well defined. For small molecules, therapeutic equivalence (TE) is assumed by demonstrating pharmaceutical equivalence (PE) and bioequivalence (BE). For biosimilars, additional data, including pharmacokinetic (PK) and (pre)clinical data are required. Unlike small molecules, biosimilars are not considered identical to the branded agent. (Image courtesy of Daan Crommelin)
The regulatory approval process for generic small molecules is well established, and generics are considered interchangeable with their branded counterpart. A separate process has been created for biologics. Similar to generics, biosimilars can be approved via an abbreviated regulatory process that usually involves pharmaceutical equivalence, pharmacokinetic, and preclinical data. Biosimilars are considered highly similar, but not identical, to the original drug.
The regulatory process for NBCDs is often conducted on a case-by-case basis. Because NBCDs cannot be fully characterized and the critical attributes required for efficacy are often unknown, it is difficult to demonstrate bioequivalence for a generic NBCD. The FDA and EMA release guidance documents for NBCD classes outlining which analyses are needed to demonstrate similarity. These documents are continually reviewed and revised.
Multi-faceted considerations for regulatory approval of biosimilars and complex drugs
Gillian Woollett stressed that the considerations for biosimilars and complex drug similars are not only scientific, but also legal, regulatory, and economic. Regulatory agencies must balance the need for scientific and clinical evidence with the need to provide patients affordable drugs in a timely manner. According to Woollett, too high a standard can be as problematic as too low a standard if it prevents access to drugs. The FDA and EMA have an additional responsibility to set a standard for the rest of the world. A product approved in the EU and US can generally be approved anywhere; however, one approved in emerging markets, such as China, Russia, and Brazil, may not be approved in other markets. In the US, only four biosimilars have been approved; however, several agents have been approved under the definition of generic biologics. In comparison, 23 biosimilars have been approved in the EU.
The considerations for biosimilars and complex drug similars are not only scientific, but also legal, regulatory, and economic.
One issue surrounding biosimilars is that they must be compared to the reference biologic approved in a given market. This can make it difficult for companies to pursue approval globally. Another issue that may need to be addressed is the addition of orphan indications to reference biologics. Because the FDA gives exclusivity for orphan indications, these indications would not be included in the biosimilar’s product label.
The FDA’s perspective on determining the equivalence of complex drugs
Wenlei Jiang described how the FDA assesses the bioequivalence of complex generics. Jiang stressed the FDA’s commitment to complex generics through the abbreviated new drug application (ANDA) approval pathway and GDUFA, which employs regulatory science initiatives for generic drugs. Specifically, Jiang showed research efforts under GDUFA that have developed new bioequivalence methods for complex drugs.
Traditional pharmacokinetic studies to demonstrate the bioequivalence of complex drugs are difficult to conduct. For some drugs, such as long-acting polymeric microspheres, which are commonly used in drug delivery, their long-acting nature would require very long studies, which may be impractical. Based on pharmacokinetic modeling research conducted by Alkermes, the FDA updated its guidance on the bioequivalence requirements for long-acting polymeric microspheres to include drug exposure up to 28 hours.
For complex drugs that act locally, such as topical skin products and nasal sprays, conventional studies that monitor drug blood levels may not be relevant. The FDA has sponsored research on new options for dermal pharmacokinetic studies, such as open-flow microperfusion (see slide).
Open-flow microperfusion can be used to monitor drug levels of topical creams in the dermis. (Image courtesy of Wenlei Jiang)
Jiang also presented a new analytic technique, morphology-directed Raman spectroscopy (MDRS), that can determine drug particle size and shape within a nasal suspension. MDRS has supported the recent approval of mometasone nasal suspension.
CHMP/EMA perspective on biosimilars
Elena Wolff-Holz described the EMA’s perspective on evaluating biosimilars and how the process has evolved over time. The EMA releases several overarching and product-specific guidelines, which are continually reviewed and revised. In a recent update to the overarching guidance (CHMP/437/04 Rev. 1), the EMA expanded the concept of a biosimilar to any biological medicinal product, including vaccines, allergens, and cell and tissue therapies, which were previously excluded. It also stressed that a biosimilar contains “a version of the active substance of an already authorized original biological medicinal product,” implying that biosimilars should not be used as reference products. In the new guidance, the goal of clinical data is to address slight differences in product characteristics, and safety and efficacy do not need to be re-established. Finally, if the reference biologic receives a new indication, the indication of the biosimilar may also be extended without the need for additional studies, if scientifically justified.
The evolution of biosimilars in the EU. New legislation is shown in red; new EMA guidelines are shown in green, and new authorizations are shown below the blue arrow. (Image courtesy of Elena Wolff-Holz)
Wolff-Holz noted that the approval process for biosimilars, which emphasizes physicochemical properties, can be difficult for clinicians, who want to know the clinical information for a drug, to accept. While clinical data for biosimilars are not included in the product’s Summary of Product Characteristics (SmPC), they are in the European Public Assessment Reports (EPAR), which clinicians are not as familiar with.
The WHO’s role in biosimilars and complex generics
Elwyn Griffiths described WHO’s role and position on biosimilars. While WHO is not a regulatory agency, it sets global standards for safety and quality. The WHO Expert Committee on Biological Standardization meets annually to establish recommendations and guidance on the quality, safety, and efficacy of biologics.
There are three major WHO guidance documents pertaining to biologics and biosimilars: Guidelines on the quality, safety and efficacy of biotherapeutic protein products prepared by recombinant DNA technology, published in 2013, Recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological medicinal products and for the characterization of cell banks, published in 2010, and Guidelines on the evaluation of similar biotherapeutic products, published in 2009.
The 2009 guidelines on similar biotherapeutics define similar biotherapeutic products (SBPs) as similar in terms of quality, safety, and efficacy to a licensed reference biological product (RBP). Similarity is established by characterizing the SBP and comparing it to the RBP in head-to-head studies. Comparison trials should be designed to detect differences in safety and efficacy between the SBP and RBP, not to establish the efficacy of the SBP. The guidelines also state that if an RBP has more than one indication, the indication of the SBP may also be expanded if scientifically warranted. One subject the WHO guidelines leave up to national regulatory agencies is whether SBPs should be considered interchangeable with RBPs.
Speaker Presentations
Video Chapters 00:00 Introduction 01:52 Complex drug products definitions 07:47 Three drug classes 13:16 What is the issue? 17:47 No access to biosimilar pathway for NBCD-similars
Video Chapters 00:00 Introduction 03:35 WHO biological standards 09:29 Regulatory oversight of biotherapeutics 15:13 WHO guidelines on evaluation of similar biotherapeutic product 23:38 Summary WHO standards
Video Chapters 00:00 Introduction 02:32 NDA versus ANDA 07:12 Consideration on PLGA sameness 13:24 Challenges for therapeutic equivalence of nasal spray products 15:13 Scientific rationale for weight-of-evidence approach 20:54 Summary
Video Chapters 00:00 Introduction 03:03 Scope includes next generation biosimilars 10:43 Manufacturing changes authorized by EMA 18:09 What if PK similarity is not convincingly demonstrated?
Video Chapters 00:00 Introduction 01:38 Working definitions for biologics 05:51 Biologic approvals have increased and are expected to rise 10:27 Biosimilars approvals across the world 18:58 Biosimilars represent a new and different business
Video Chapters 00:00 Introduction 00:50 Thoughts on the definition of the API and does it need to be updated 05:48 Measuring release of drugs 07:40 Critical factors, quality attributes for complex drugs 17:51 Looking forward to how further complexity affects biological responses 21:49 IP and open data review in a profit-driven industry
Comparisons of Copaxone (glatiramer acetate injection) with Its Generic Glatopa (glatiramer acetate injection)
Speakers
Joseph Glajch Momenta Pharmaceuticals
Iris Grossman Teva Pharmaceuticals
Andre Raw U.S. Food and Drug Administration
Highlights
Glatopa (glatiramer acetate injection), an FDA-approved generic of Copaxone(glatiramer acetate injection) is considered similar to the branded product based on the tests required by the FDA.
Additional comparisons have revealed differences between the drugs that may affect safety and efficacy.
Glatopa: a complex generic drug for multiple sclerosis
Glatopa was approved by the FDA in 1996 as a generic version of Copaxone for the treatment of multiple sclerosis. These drugs consist of glatiramer acetate, a complex mixture of polypeptides produced by polymerizing four amino acids and then partially depolymerizing the resulting peptides.
Scientific considerations to approaching complex generics
Andre Raw discussed the scientific considerations to approaching generic versions of Copaxone (glatiramer acetate) and Lovenox (enoxaparin sodium) injections, two of the complex active ingredients recently approved in generic versions by the FDA. Raw argued that understanding the nature of the complexity of these drugs is key to evaluating generic similars. For instance, the complexity of Copaxone comes from the polymerization of activated amino acids, which determines the sequences of the polypeptides, and the subsequent partial depolymerization.
To ensure similarity of Copaxone and Lovenox similars, the FDA drafted guidance listing four criteria that generic products must meet. First, the pharmaceutical company must demonstrate equivalence in its reaction scheme. Second, the FDA places constraints on several physicochemical properties, such as molecular weight distribution and amino acid composition. This also means that the structural signatures, which reflect the polymerization and depolymerization processes, and biological assays will be similar as well.
The third criterion requires that generic manufacturers identify “process signatures;” equivalence in these signatures ensures that the generic active ingredient is manufactured with effectively the same polymerization kinetic and cleavage biases as the brand name. Finally, the fourth criterion relies on the equivalence of biochemical and/or biological markers for activity to ensure sameness. Unlike the previous three criteria, which in their aggregate ensure equivalency of molecular diversity, this criterion serves as a confirmatory test to ensure equivalency in functional biochemical or biological markers.
Comparison of Copaxone and Glatopa for FDA approval
Joseph Glajch described the tests that Sandoz conducted to demonstrate the equivalence of Glatopa and Copaxone. In approximately 50 physiochemical and 10 biological tests, Glatopa fell within an acceptable range considered to be equivalent to Copaxone. Glajch stressed that these analyses must be conducted on dozens of lots to understand the diversity and variability within the drug. He showed the data from some of these analyses, including molecular weight distribution, amino acid composition, and structural signatures. He also showed that the drugs have similar effects on disease intensity in a model of autoimmune encephalomyelitis and similar results on histamine release from cells.
Additional comparisons of Copaxone and Glatopa
While Raw and Glajch showed that Glatopa and Copaxone are similar according to the methods required by the FDA, Iris Grossman described studies using higher-resolution techniques conducted by Teva Pharmaceuticals that reveal differences in surface charge and molecular weight density and distribution. In addition, Glatopa had greater batch-to-batch variability in these characteristics than Copaxone.
Copaxone and Glatopa are similar based on the physicochemical tests required by the FDA (rows 1, 2, and 4). However, other, higher-resolution methods demonstrate differences. (Image courtesy of Iris Grossman)
These differences may have consequences on efficacy and safety. In mice, of the thousands of genes affected by Glatopa and Copaxone, approximately 10% were different between the two drugs. The genes that differed were involved in pathways important for efficacy, including inflammation and immune response.
Based on these results, Teva has submitted comments on the draft FDA guidance on glatiramer acetate injections.
Speaker Presentation
Video Chapters 00:00 Introduction 02:37 Physicochemical differences relevant to mode of action 10:22 Relevance of differences to function and safety 13:50 Immunological triad 17:25 Functional effects summary and conclusions
Issues with Iron Carbohydrate Similars
Speakers
Beat Flühmann Vifor Pharma Ltd
Stefan Mühlebach, PhD Vifor Pharma Ltd
Panel Discussion Moderator:
Daan J.A. Crommelin Utrecht Universit
Highlights
Several approved generics of iron carbohydrate complexes are not as effective as their branded counterparts.
Hospital pharmacists are not aware of the differences between iron carbohydrate products and often substitute these products without informing a patient’s physician.
Iron carbohydrate similars
Iron carbohydrate products are used to treat anemia in patients with chronic kidney disease. Several iron carbohydrate generics were approved in Europe in the mid-2000s. According to Stefan Mühlebach, there was no regulatory process for complex similars at this time, and the drugs were approved via the small molecule generic route. Researchers and regulators were not aware that the active pharmaceutical ingredient was not fully characterized, and iron carbohydrate similars were deemed identical to and interchangeable with the original drugs without additional efficacy or safety studies. Since then, real-life clinical studies have shown that show the approved iron carbohydrate similars are not clinically identical to the original formulations.
The EMA and FDA have reacted to these data and have published several guidance papers on iron carbohydrate similars.
The hospital pharmacist’s approach to iron complex carbohydrates
Beat Flühmann of Vifor Pharma described the pharmacist’s perspective of complex generics using iron sucrose, a type of iron carbohydrate, as an example. In a survey hospital pharmacists in France and Spain, Flühmann found that pharmacists substitute 30% to 50% of branded iron sucrose prescriptions with a generic version. Approximately 40% of pharmacists believed that the products have the same efficacy and safety, while the remaining 60% had no opinion. In addition, many pharmacists did not inform the physician that they had dispensed the generic version.
Despite clinical data that show significant differences in efficacy and safety among iron sucrose similars, most pharmacists are not aware of these differences. (Image courtesy of Beat Flühmann)
Flühmann stressed the importance of educating pharmacists on the differences in biosimilars and complex generics. Vifor conducted a roundtable discussion earlier this year with leading hospital pharmacists throughout Europe to discuss how to select nanosimilars for hospital formularies. The roundtable added several criteria for hospital formulary committees to consider when selecting a nanosimilar, including particle size and size distribution, pharmacokinetics, and stability of ready-to-use formulations.
Speaker Presentations
Video Chapters 00:00 Introduction 04:40 Therapeutic equivalence from manufacturing to efficacy and safety 09:32 Current situation for follow-on approval 14:48 NBCD product evaluation 18:32 Landscape of drugs follow-ons
Video Chapters 00:00 Introduction 03:11 Making biosimilars available globally 08:25 The unbound drug vs release and release mechanisms 12:11 Interchangeability and acceptability in the market 16:27 Proposed systems for biosimilars and for currently approved biologics 20:12 Concluding thoughts
Other Case Studies of Complex Generics
Speakers
Kouros Motamed NantBioScience, Inc.
Chetan Pujara Allergan
Gary West Azaya Therapeutics
Highlights
The bioequivalence of Cynviloq, a polymeric micelle formulation of the chemotherapy paclitaxel, and Abraxane (paclitaxel protein-bound particles for injectable suspension), an approved albumin-bound paclitaxel, is being investigated in the study TRIBECA.
Robust criteria are needed to ensure the equivalence of different ophthalmic emulsions.
Greater harmony between the FDA and EMA could streamline the approval of a generic version of Doxil (doxorubicin HCl liposome injection).
Cynviloq: a new formulation of paclitaxel
Kouros Motamed discussed a polymeric micelle formulation of the chemotherapy paclitaxel, Cynviloq, which is approved in several Asian countries for breast and lung cancer under the brand name Genexol-PM. These approvals were based on comparisons to Taxol (paclitaxel), a formulation of paclitaxel containing the excipient Cremophor EL. In the US and EU, approval requires comparison to Abraxane, an albumin-bound formulation of paclitaxel approved for breast, lung, and pancreatic cancer.
Evolution of paclitaxel therapies. (Image courtesy of Kouros Motamed)
In in vitro studies, Abraxane and Cynviloq had similar pharmacokinetic properties at therapeutic doses. At higher doses, the Abraxane concentration sharply increased, resulting in increased toxicity. The concentration of Cynviloq, however, did not increase as quickly, and therefore may be less toxic at higher doses.
A pharmacokinetic bioequivalence study, TRIBECA, was conducted in patients with metastatic breast cancer. Sorrento Therapeutics issued a press release stating that TRIBECA demonstrated bioequivalence of Abraxane and Cynviloq. In 2015, Cynviloq was acquired by NantWorks and has been renamed Nant-paclitaxel.
Demonstrating equivalence of ophthalmic emulsions
In 2013, the FDA released draft guidance on cyclosporine emulsions. To test whether this guidance was sufficient, Allergan tweaked its manufacturing process to make nine cyclosporine emulsions similar to Restasis (cyclosporine ophthalmic emulsion). Chetan Pujara showed that although these emulsions met the FDA criteria for similarity, there were key physicochemical and biological differences. For example, the cyclosporine distribution between the phases of the emulsion varied between the drugs. This corresponded with differences in the drug’s ability to permeate human corneal cells. Allergan also saw variability in the amount of cyclosporine in tears in rabbits.
The updated FDA guidance, released in 2016, incorporates suggestions by Allergan based on these data. However, Pujara stressed that further research on linking in vitro results to in vivo performance and on robust methods to characterize emulsions is still needed.
Regulatory barriers to a generic version of Doxil
Gary West called for harmony between regulatory authorities, citing the recent difficulties that Azaya Therapeutics has had in gaining approval for its generic doxorubicin. Doxorubicin, a treatment for ovarian cancer, is marketed by Janssen in the US under the brand name Doxil and in the EU under the brand name Caelyx (pegylated liposomal doxorubicin hydrochloride for injection).
Can international regulatory agencies work together to remove barriers facing approval of generic drugs?
Currently, Caelyx is the reference drug for doxorubicin in the EU. In the US, the FDA established a generic version of doxorubicin, ANDA 203263, as the reference drug for doxorubicin due manufacturing concerns with Doxil. However, the FDA discovered that the plant manufacturing the generic version was not complying with several guidelines, which led to contamination. West argued that due to these issues, the FDA-approved doxorubicin generic may not be the best comparator. He showed certificates of analysis from the sole manufacturer that made both Caelyx and Doxil in 2013 that demonstrate that, at that time, the two drugs were the same product with a different label and argued that they should therefore be considered interchangeable by regulatory agencies.
Azaya Therapeutics’ investigational doxorubicin generic, dubbed ATI-0918, was shown to be bioequivalent to Caelyx. However, because the EMA requires that Caelyx be sourced within the EU, and the FDA requires generics to be compared against the reference standard ANDA 203263, the company faced regulatory hurdles from both agencies. West called upon the agencies to work together to remove the barriers facing approval of generic drugs.
Speaker Presentation
Video Chapters 00:00 Introduction 03:21 A triple-down, unintended, regulatory catch 22 09:52 Lipodox versus Sun product 18:28 Regulatory barriers 22:29 Conclusions
Analytical Techniques for Characterizing Complex Drugs
Speakers
Stephan Stern Nanotechnology Characterization Laboratory
Wyatt Vreeland The National Institute of Standards and Technology
Highlights
Choosing the right analytical method is important when measuring the size of nanoparticles.
A new method to measure plasma drug concentration for nanomedicines is being validated by the NCL.
Techniques to measure nanoparticle size
Wyatt Vreeland described the advantages and disadvantages of several techniques to measure nanoparticles size.
The most common technique for measuring nanoparticle size is batch light scattering. In this method, the particle size is determined based on their ability to scatter light waves. This method is quick, simple, and nondestructive. However, because larger particles scatter light much more than smaller particles, a small amount of large particles can drown out the signal due to smaller particles, resulting in significant errors.
To avoid this complication, mixtures can be separated by size by either size-exclusion chromatography (SEC) or field flow fractionation (FFF) and then measured by light scattering. One advantage of FFF over SEC is that it can separate delicate or soft colloidal particles, which are often components of complex drugs. FFF can be used to separate particles of a few nanometers to 1000 nanometers.
Vreeland also discussed several new techniques that measure particle size by monitoring individual particles. In nanoparticle tracking analysis (NTA), particles are imaged directly with a laser, and their size is determined by tracking the extent of diffusion over time. While NTA is a robust tool to measure particle size, it is only effective within a narrow concentration range. A second technique, resonant mass measurement measures the change in frequency a particle causes as it flows through a vibrating cantilever. In addition to size, this technique, unlike others, can also measure buoyant density; however the cantilever is prone to clogging and cannot be used to measure liposomes. Finally, electrical sensing zone measures the change in electrical conductivity as a particle travels through a pore between two electrodes. This technique is similar to Coulter counter, which is used to measure bacteria and viruses. This is a very new technique for nanoscale particles.
A new method to measure nanomedicine plasma levels
The concentration of drugs administered via nanoparticles can be divided into three forms: the nanoparticle-encapsulated form, the unencapsulated free form, and the unencapsulated protein-bound form. Current methods to separate the encapsulated from unencapsulated drug promote un-encapsulation and do not differentiate protein-bound from encapsulated drug.
In two pharmacokinetic studies of Caelyx, the measured levels of unencapsulated drug differed by 6-fold, while the levels of unencapsulated drug differed by almost 12-fold, likely due to problems in fractionation methods.
Stephan Stern presented a new stable isotope tracer technique being developed by the NCL to separate and measure nanomedicine drug fractions. NCL is working with the FDA to evaluate this method for determining the bioequivalence of generic nanomedicines. As part of this effort, the NCL is conducting in vitro bioanalytical studies as well as bioequivalence studies in rats of Abraxane and Genexol-PM, discussed by Motamed, and doxorubicin HCl and Doxil, discussed by West.
In the stable isotope tracer method, an isotopically-labeled drug is added to the blood sample. The free and bound drug forms are then separated through a semi-permeable membrane. The percentage of labeled drug that does not pass through the membrane is used to determine the percent of bound drug, which can then be used to calculate the concentrations of bound and unbound drugs. (Image courtesy of Stephan Stern)
Speaker Presentations
Video Chapters 00:00 Introduction 03:48 Nanomedicine pharmacokinetics 08:39 Sources of intra-subject variability 13:43 Novel stable isotope tracer method 19:26 Measuring unbound drug in evaluating nanomedicine pharmacokinetics
Video Chapters 00:00 Introduction 02:50 Batch light scattering 08:11 How laminar flow works in FFF 13:18 Dynamic light scattering 17:52 Resonant mass measurement 20:18 Future directions
Open Questions
How can researchers determine the critical attributes for complex drugs?
What are the best methods to characterize complex drugs?
What are the most appropriate pharmacokinetic methods to evaluate bioequivalence of complex drugs?
Should biosimilars and complex generics be considered interchangeable with their branded counterparts? What criteria are necessary to demonstrate interchangeability?
How can regulatory agencies balance the need for robust scientific and clinical evidence with the need for affordable medications when evaluating complex generics?
How can regulatory agencies reach agreements on how to evaluate complex drugs?
How can companies and regulatory agencies communicate the potential clinical differences between original and generic complex drugs?
Teva Pharmaceuticals Industries Ltd. [press release] Teva Files Citizen Petition with the U.S. Food and Drug Administration (FDA) Regarding the Complexity of COPAXONE® (glatiramer acetate) Following the Agency’s Guidance. July 3, 2014.
Wenlei Jiang
Babiskin A et al. Pharmacokinetic modeling and simulation of naltrexone for extended-release injectable suspension to derive alternative BE metrics. ACoP. 2015.
Ambardekar and Stern. NBCD Pharmacokinetics and Bioanalytical Methods to Measure Drug Release. In Daan Crommelin D and de Vlieger J (ed) Non-Biological Complex Drugs; the Science and Regulatory Landscape. Springer, New York, NY; 2015: In-press.
Charles Serhan’s groundbreaking research is changing the way we view inflammation and the strategies for its therapeutic resolution.
Published October 1, 2016
By Daniel Radiloff
The 2016 Ross Prize in Molecular Medicine was awarded to Charles N. Serhan, PhD, DSc, who serves as the Simon Gelman Professor of Anesthesia, Perioperative and Pain Medicine at Harvard Medical School and Professor of Oral Medicine, Infection and Immunity at Harvard School of Dental Medicine.
Dr. Serhan received the Award, which is conferred by the Feinstein Institute for Medical Research and Molecular Medicine, at a scientific symposium held at the Academy on June 13, 2016, in his honor. A pioneer in the field of inflammation resolution research, Dr. Serhan was the first researcher to identify anti-inflammatory cellular mediators, including resolvins and lipoxins, which are critical in regulating the pro-inflammatory pathway. These discoveries have paved the way for increased understanding of how the resolution of inflammation can be translated into therapies for a variety of human diseases.
We sat down with Dr. Serhan to discuss the award, the scope and impact of his research, and the importance of mentorship in developing the next generation of scientists.
What is the current research focus of your laboratory?
The main research focus of the lab is the elucidation of the mechanisms involved in the resolution of inflammation and structural elucidation of the mediators in order to understand organ protection and collateral tissue damage, as this is the basis of many diseases and the collateral stress and damage for surgical interventions.
How did you choose mediators of the inflammatory response as the basis of your work?
I have always been interested in chemistry and biochemistry. The notion of chemical mediators orchestrating the immune response intrigued me from learning about things like histamines and the early prostaglandin research. You could say I have stuck with this research through my entire career, as there were enough questions to ask to go deeper and deeper which led to resolution, which no one had really studied before in a mechanistic fashion.
What was the “eureka” moment, when you realized that your research on these pathway could be used for therapeutic purposes?
It has been a steady progression. I have to say that at one point I did have an epiphany about the whole system—that it was a straight line that has yet to be fully realized, and we could use each one of the mediators we have identified to serve as a backbone for therapeutics. I would say another moment was rewriting the errors in the biochemistry textbooks on how essential fatty acids were actually regulating inflammatory responses. Overall, it has been an incremental process and a lot of slow, hard work—more than one moment.
What will be the next injury whose treatment will be influenced by your and others’ research in the inflammation field?
The stress of surgery is well recognized among surgeons as an acute inflammatory response, as is reflow injury, when blood reflows to tissue. These are two areas we can have a big impact on. Demonstrations are currently underway at a clinical trial level focused on ocular dry eye inflammation using a resolvin E1 mimetic. This work is based on a company I was involved in starting in 2000, but I am no longer actively involved in this venture.
Additionally, an orphan disease of great public health importance focused on by my lab is periodontal disease, which is inflammation-induced bone loss around the peridontium. We were able to go from a mouse model to a rabbit model thanks to NIH funding and have been able to develop a GMP-synthesis and pro-resolving mouth rinse.
A trial is on, with more than sixty people enrolled at the Forsyth Institute, to see if we can stimulate resolution of inflammation in the early stages of periodontal disease. This is being done in collaboration with Tom Van Dyke and his colleagues at the Forsyth Institute, with support from NIH/NIDCR. So I have a focus in my lab on periodontal disease, thinking that if we control local inflammation, what would be the impact on systemic inflammation. There is evidence in a lot of papers showing links to all sorts of systemic diseases resulting from periodontal disease.
What do you hope will be the long-term impact of your research from a global perspective?
One aspect we haven’t really touched on, but which is really important, is having a better education about the role of nutrition in an appropriate innate immune response. Some of our work underscores how important fatty acid nutrition is—a different side of our work that is still very important.
Did you always envision yourself as a scientist, or did you dream of being something else as a youth?
As you know, no one really sees themselves as a geek growing up. I really enjoyed chemistry when I was younger, tinkering around with chemistry sets and microscopes, but as I got older really wanted to be a musician. I even spent time on the road touring with bands, but I had a very swift change of heart and went back to my roots, deciding to study biochemistry at Stony Brook, and had a great experience as an undergraduate. Today, I still don’t really see myself as a scientist but rather a biomedical investigator. I always have seen scientists as people who work on rocket ships.
Do you think your musical training has had any influence on how you approach scientific research?
Yes, most definitely, it does play a role in science. The way I organize the laboratory projects is analogous to orchestration of music. Also, I would compare developing patience, skill and rigor in the scientific process to developing musical skills through continual practice. The more proficient you become mastering scales and rudiments in music, the more confident you become in your skills, and I see scientific research the same way.
Were there any individuals in your life that steered you towards science or played an important role in you becoming a scientist?
Yes, I had great science teachers in elementary school and absolutely loved them and loved science. When I was at graduate school at NYU I frequently visited high school science classes and told them how exciting scientific research was.
Were there any major challenges you had to overcome in your career to becoming a successful scientist?
Oh yeah, trying to remain continually funded is a real challenge. Other than that, overall, I have been very lucky, having great mentors and a supportive family. I’ve also had great trainees over the years, with about 90% of them successfully moving on to the next steps in their career.
Speaking of mentors, what is the most valuable lesson that you have learned from your mentors over the course of your career?
Anyone that does reasonably well in science has to have not only one mentor but a half a dozen mentors. I was lucky enough to work with the Lasker Award Winner Michael Heidelberger, the father of immunochemistry, when I started graduate school at NYU, who was retired at the time and in his 80s.
I learned two things from him that made a large impact on me: 1. You have to work on something you love to get you through the difficult times, and 2. You have to write everything down and make observations, because you will get distracted and forget things. To this day, I make people in my lab have two notebooks—an electronic one for detailing their experiments and one for writing down their ideas.
What do you hope that your mentees will pass along to their own mentees one day?
Of course, almost everyone would say the passion for experiments, but I would say steadfastness, commitment, and rigor are the key, because there are many things that can lead you astray these days.
What does winning the 2016 Ross Prize in Molecular Medicine mean to you?
I can’t even find the words to express it, I am so humbled and makes me very proud. On a personal level it’s nice for the people in my lab as they can see something to aspire to.
As the Academy approaches its bicentennial, we’re reaching out to top minds in emerging fields to get their opinions on the future of the sciences. What emerging fields do you think are the most exciting?
That’s a hard one. There are a lot of emerging areas of science that are exciting. Science drives technology and technology drives science. Lately, I have been working on tissue regeneration, and am interested in nanotechnology and local drug delivery systems, and I believe these approaches will revolutionize medical treatment and improve life. Also, from my perspective, I would say personal metabolomics is another emerging field, which may help us to understand collective health and behavior as well as personalized medicine.
About the Ross Prize in Molecular Medicine
The annual Ross Prize in Molecular Medicine was established in 2013 in conjunction with the Feinstein Institute for Medical Research and Molecular Medicine. The winner is an active investigator who has produced innovative, paradigm-shifting research that is worthy of significant and broad attention in the field of molecular medicine.
This individual is expected to continue to garner recognition in future years, and their current accomplishments reflect a rapidly rising career trajectory of discovery and invention. The winner receives an honorarium of $50,000. Previous Award winners include: Lewis C. Cantley, PhD, Weill Cornell Medical College (2015); John O’Shea, MD, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (2014); and Dan Littman, MD, PhD, New York University (2013).
From study design to patient engagement, Gary Bennett, PhD, shares his insight on what is and is not effective in applying technology to obesity research.
The need for interventions to prevent and treat obesity is extremely urgent, as over one-third of adults and 17% of children in the United States are considered to be obese based on body mass index (BMI). From wearable devices to smartphone applications for tracking diet and exercise, consumer technologies are aiming to make a positive impact on changing lifestyle behaviors and potentially decreasing obesity rates.
Gary Bennett, PhD, of the Duke Global Digital Health Science Center, is bringing digital health to obesity interventions to measure and evaluate the effectiveness of technology in increasing patient engagement and improving long-term health outcomes, such as weight maintenance. Recently Dr. Bennett shared some of his best practices when designing studies applying technology to obesity interventions, surprising study results on weight and co-existing conditions, and the most promising element for obesity tech research (that is also commonly ignored).
Considering User Engagement
According to Dr. Bennett, one of the most significant mistakes made in research on health technology and patient engagement is not taking into consideration the user experience. “We as researchers can easily get hyper-focused on theory, evidence, and innovative new functionality. However, apps are only useful if they’re actually used by patients,” he stated. User engagement is the best predictor of positive outcomes, which is why it is so important to manufacturers of consumer technology.
“Commercial smartphone application developers are constantly testing and iterating through design and functionality changes to optimize user engagement. The (research) field far too frequently adopts the ‘someone-can-make-it-pretty-later’ approach, which results in outcomes that underestimate their true effect.” Dr. Bennett also noted that creating more consumer technologies isn’t necessarily the solution to increasing patient engagement and improving health outcomes. “The existing suite of apps do a fine job of collecting data, but they’re less useful for changing behavior. What we need are creative, theory- and evidence-based tools that integrate with existing apps and leverage their data to improve patient outcomes and make clinical care (whether that’s from a primary care provider or other clinician) more efficient and effective.”
Gary Bennett, PhD
Surprising Results, Long-term Outcomes
Dr. Bennett’s research on technology and obesity has led to some surprising results with long-term outcomes. “Our Shape trial was a test of weight gain prevention app for medically vulnerable patients in primary care. Many in this group have exceedingly high obesity risk, but very little interest in weight loss. We predicted that the app would help patients avoid weight gain during the 18-month trial. However, we were surprised to find that they kept the weight off for up to four years.”
A second unexpected outcome was a nearly 70% decrease in depression among patients with high rates of depression at the start of the study, he added. The relationship between depression and obesity has been suggested to be a reciprocal one, as obesity has been shown to increase the risk of depression and depression to be predictive for developing obesity.
When it comes to a promising consumer technology for obesity research, for Dr. Bennett the most encouraging one is one we take for granted-human beings. “Nearly all of our apps work better when combined with human coaching, counseling, or care. Although most thought that digital health technologies would render us humans irrelevant, we’re now finding that they’re most useful-particularly with complex conditions like obesity-in making clinical care more efficient and effective. Ultimately, we should be focused on the data, using it to better deliver real-time personalized feedback, reminders, and notifications to patients, while identifying the ways that it can best inform clinical care.”
The processes associated with aging may be risk factors for age-related diseases. Conversely, many age-related chronic diseases accelerate aging. However, because most research is focused on specific diseases, the broad mechanisms of disease as a driver of aging have not been well studied. Understanding how disease drives aging could not only help people live longer but also improve health and quality of life during old age.
On April 13–14, 2016, researchers studying aging and three disease areas—HIV/AIDS, oncology, and diabetes—met at the New York Academy of Sciences for the Disease Drivers in Aging: 2016 Advances in Geroscience Summit. The meeting expanded on the National Institutes of Health’s 2013 Advances in Geroscience Summit, examining how chronic diseases and their treatments affect aging. The meeting also aimed to stimulate collaboration between researchers studying aging and researchers studying disease. The summit was presented by the Gerontological Society of America, the American Federation for Aging Research, the Trans-NIH GeroScience Interest Group, and the New York Academy of Sciences.
The meeting opened with four keynote presentations from geroscience researchers, followed by a series of short talks and panel discussions featuring researchers focused on HIV/AIDS, diabetes, and cancer. This eBriefing reviews the panel discussions on each disease area and the overarching discussion on common themes and ideas for collaboration between researchers studying aging and disease.
Presentations available from:
Timothy Ahles, PhD (Memorial Sloan Kettering Cancer Center) Kathryn Anastos, MD (Albert Einstein College of Medicine) Steven Austad, PhD (University of Alabama at Birmingham) James Becker, PhD (University of Pittsburgh) Caroline Blaum, MD (New York University) Judith Campisi, PhD (Buck Institute for Research on Aging) Harvey J. Cohen, MD (Duke University) Wendy Demark-Wahnefried, PhD (University of Alabama at Birmingham) Jan van Deursen, PhD (Mayo Clinic) Elissa Epel, MD (University of California, San Francisco) Kristine Erlandson, MD (University of Colorado) Brooke Grindlinger, PhD (The New York Academy of Sciences) Jeffrey Halter, MD (University of Michigan) Richard Hodes, MD (National Institute on Aging, NIH) Peter Hunt, MD (University of California, San Francisco) Beth Jamieson, PhD (University of California, Los Angeles) C. Ronald Kahn, MD (Joslin Diabetes Center) Balakuntalam Kasinath, MD (University of Texas Health Science Center) Gretchen Neigh, PhD (Virginia Commonwealth University) Rosario Scalia, MD, PhD (Temple University) Marissa Schafer, PhD (Robert and Arlene Kogod Center on Aging) Felipe Sierra, PhD (National Institute on Aging, NIH) Mary Sehl, MD, PhD (University of California, Los Angeles) Christopher Wiley, PhD (Buck Institute for Research on Aging) Panel Discussions
Presented by
How to cite this eBriefing
The New York Academy of Sciences. Disease Drivers of Aging: The 2016 Advances in Geroscience Summit. Academy eBriefings. 2016. Available at: www.nyas.org/Geroscience2016-eB
Media
00:01 1. Introduction and overview 04:25 2. What we know from basic research 11:58 3. Progress made; What we want to know; Conclusion
00:01 1. Introduction and overview 08:20 2. Chronic stress and cell aging 13:04 3. Telomeres and disease risk 15:55 4. Disease drivers; Conclusion
00:01 1. Presentation by Beth Jamieson 10:20 2. Presentation by James Becker 19:52 3. Presentation by Gretchen Neig
00:01 1. Presentation by Kathryn Anastos 10:16 2. Presentaton by Peter Hunt 20:23 3. Presentation by Kristine Erlandson
00:01 1. Introduction; HIV and aging 08:25 2. HIV and macrophages; Primate studies; Where to intervene 16:21 3. Maximizing control group resources; Biomarkers for stress 23:48 4. Regarding Alzheimer’s; Mitochondrial dysfunction; Aging and viral dormancy; Data set creation 28:56 5. Supressor mutations; Cognitive dysfunction; Conclusion
00:01 1. Presentation by Marissa Schafer 11:07 2. Presentation by Christopher Wiley 22:09 3. Presentaton by Mary Sehl
00:01 1. Presentation by C. Ronald Kahn 10:29 2. Presentation by Balakuntalam Kasinath 20:47 3. Presentation by Rosario Scalia
00:01 1. Presentation by Caroline Blaum 10:35 2. Presentation by Jeffrey Halter
00:01 1. Treatment with CDK4 inhibitors; What is accelerated aging? 09:03 2. Increased phosphorylation; Obesity, asthma, and diabetes 13:55 3. Amino acids and insulin secretion; More on accelerated aging 18:52 4. Regarding astroglial cells; The blood-brain barrier 26:40 5. Treatment with metformin; Diabetes and immunodeficiency; Rapamycin; Conclusion
00:01 1. Introduction; Choosing the right journal 04:20 2. General manuscript preparation; Discussion and introduction 11:44 3. The abstract; The title 14:38 4. Authorship; The cover letter 21:44 5. Referees; Peer review 27:44 6. Decisions; Common reasons for rejection; Revision and resubmission 34:35 7. Preparing a response; Appealing a negative decision 39:12 8. Parting thoughts; Conclusion
00:01 1. Presentation by Jan van Deursen 11:48 2. Presentation by Harvey Jay Cohen 22:09 3. Presentation by Judith Campisi
00:01 1. Presentation by Wendy Denmark-Wahnefried 10:29 2. Presentation by Timothy Ahles
00:01 1. Introduction 07:48 2. Synergy between aging and cancer research models; Aging in animal models 17:30 3. Disease interplay across disciplines; Dietary restriction; Senescent T-cells 24:12 4. Computational and systems biology; Chemotherapy and senescence; Funding 31:11 5. Anti-depressants before chemo; Intervention 40:15 6. Regarding exosomes and evolution; Conclusion
00:01 1. Panelists’ opening remarks 13:17 2. Disease treatment and lifespan extension; Targeting senescenct cells 21:06 3. Embracing complexity; Developmental manipulation in aging research; Inflammation 33:20 4. Review and funding 41:00 5. Metabolic reprogramming; Healthspan vs. lifespan; Regarding data sets 48:18 6. Mitochondrial dysfunction; Going forward; Common tools 61:28 7. Aging as disease; Stress and trauma; Drug discovery; Influence of local environment 69:28 8. Exercise; Incentivizing collaboration; Policy and funding 82:06 9. Focus on gene expression; Big data; Public perceptions 87:27 10. Cohort development; Conclusion
Sierra F, Kohanski R (eds). Advances in Geroscience. Springer International Publishing. 2016. [Ebook] Provides a comprehensive overview of geroscience.
General aging resources: journal articles
National Institute on Aging (NIA) NIA, one of the 27 Institutes and Centers of NIH, leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life.
Jennifer Cable lives in New York City, where she experiments with different outlets to communicate science. She enjoys bringing science to scientists and nonscientists alike. She writes for Nature Structural and Molecular Biology, Bitesize Bio, Under the Microscope, and the Nature New York blog. She received a PhD from the University of North Carolina at Chapel Hill for her research in investigating the structure/function relationship of proteins.
Funding for the eBriefing of this conference was made possible, in part, by 1 R13 AG 053043-01 from the National Institute on Aging. Co-funding has been provided by the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Cancer Institute. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.
This activity is supported by an educational grant from Lilly. For further information concerning Lilly grant funding visit www.lillygrantoffice.com
Although age is an important variable in clinical research, the effects of aging are often understudied.
Improving the quality of life during aging is as important as increasing longevity.
Short-term stress can promote resilience to aging; however, chronic stress accelerates aging.
Introduction
Aging is often accompanied by chronic diseases including heart disease, cancer, diabetes, and Alzheimer’s disease, to name a few. Many processes associated with aging may be risk factors for these diseases. While aging occurs in the absence of disease—a steady decline in health is expected as a person ages—chronic diseases also accelerate aging, exacerbating normal physical and cognitive decline.
As people age, a steady decline in health is expected (red line). Some diseases cause a temporary decrease in health followed by full recovery (first black dip). However, other diseases can change the trajectory of aging, leading to a faster decline in health (fuchsia line). (Image courtesy of Felipe Sierra)
The field of geroscience has focused on how aging affects disease, and this topic was the theme of the first geroscience summit, “Advances in Geroscience: Impact on Healthspan and Chronic Disease,” which took place in October, 2013, in Bethesda, Maryland. Papers related to that summit were published in a supplement to the Journals of Gerontology in June, 2014. However, the reverse question—how disease affects aging—has gone largely unstudied, and this topic was the theme of this 2016 meeting.
The 2016 summit examined how three diseases—HIV/AIDS, diabetes, and cancer—affect the major pillars of aging established at the first Geroscience Summit: macromolecular damage, stress response, epigenetics, stem cells, proteostasis, inflammation, and metabolism.
The meeting opened with four keynote presentations from geroscience researchers who described successful interventions to delay aging and increase life span in animal models. They also noted the need for multidisciplinary research, challenging attendees to work across disease states. Understanding common mechanisms in aging and chronic diseases could help people live not only longer but also healthier lives.The keynote presentations were followed by a series of short talks and panel discussions featuring researchers focused on HIV/AIDS, diabetes, and cancer. This eBriefing reviews the panel discussions on each disease area and the overarching discussion on common themes and ideas for collaboration between researchers studying aging and disease.
The seven pillars of aging. (Image: Kennedy BK et al., Cell 159: 709-713 [2014])
A multidisciplinary approach to aging
Richard Hodes of the National Institute of Aging (NIA) outlined the multidisciplinary structure at the NIA and National Institutes of Health (NIH) to raise awareness of the role of aging in disease and to fund aging-based research. Targeting aging may reduce the incidence of age-related diseases. The divisions of the NIA span basic biology to clinical and behavioral studies. Because aging touches so many fields, the NIH also created the Geroscience Interest Group (GSIG), with members from 21 institutes. Hodes called on researchers to step outside the silos of their specialties and to study features of aging common to disparate disciplines and diseases.
Hodes also presented evidence of the importance of considering age when choosing treatments for patients, and highlighted the need to include elderly subjects in preclinical and clinical studies. In the Diabetes Prevention Program, both medication and lifestyle changes reduced the risk of developing diabetes in at-risk patients younger than 60 years. However, in subjects older than 60, only lifestyle changes were effective. In a pre-clinical study, elderly mice with cancer died sooner when given immunotherapy than those who did not receive treatment.
Felipe Sierra, also from the NIA, pointed to the need to re-examine our approach to disease. The elderly often present with several comorbidities. Instead of considering each disease individually, researchers should consider interactions between diseases, and between disease and aging.
The keynote speakers also described efforts to promote aging research. In late 2015, the NIA released a request for applications to test whether the age of laboratory animals affects outcomes in studies investigating disease. In the NIA’s Interventions Testing Program (ITP), researchers can submit compounds to be tested for an effect on extending life span in mice.
Increasing health span as well as life span
Steven Austad of the University of Alabama at Birmingham emphasized that increasing longevity is not the same as improving health. Several interventions can extend life span in animals. In some cases, such as the use of rapamycin in mice, health span is also improved. Indeed, rapamycin extends life and delays Alzheimer’s disease, cancer, atherosclerosis, and heart dysfunction in mice. However, genetic mutations that increase life span in the worm Caenorhabditis elegans do not extend the period of good health. Furthermore, life-extending interventions are not without side effects. In mice, dietary restriction and rapamycin have been linked to low bone density, immunosuppression, cataracts, diabetes, and hyperlipidemia.
Life expectancy (gray) and health expectancy (blue) of men and women at age 65. An increase in life span does not always correlate with improved health. (Image: Kennedy BK et al., Cell 159: 709-713 [2014])
Longer human life expectancy with improved treatments for fatal diseases often comes at the cost of declining quality of life and increased disability—Alzheimer’s disease, dementia, frailty, vision loss, pain, joint replacement, and other conditions. Treating the underlying causes of aging may prevent this deterioration in quality of life.
Telomere length as a marker of aging
Elissa Epel of the University of California, San Francisco, discussed the relationship between stress and cell aging. Epel uses telomere length—stretches of repeat DNA at the end of chromosomes—as an indicator of aging. Chronic disease can accelerate telomere attrition; while there are myriad biochemical alterations in each disease, many diseases of aging feature the triad of oxidative stress, inflammation, and hyperglycemia / insulin resistance. For example, in diabetes the disease processes of impaired β-cell function, and resulting higher levels of biochemical stressors, further shorten telomeres.
Psychiatric diseases, particularly major depression and anxiety disorders, are also associated with shortened telomeres. Given the high comorbidity of medical and psychiatric conditions, Epel noted, it is important to consider that depression may affect aging biology, not just the physical disease condition. Treatments for diseases may further affect the rate of telomere attrition, either speeding it up or slowing it down. For example, statins and possibly metformin, used in diabetes treatment, may prevent telomere attrition, while HAART therapy in HIV may accelerate telomere attrition. Chemotherapy can work through telomere damage of cancerous as well as healthy cells. Childhood traumas followed by chronic stressors in adulthood result in shortened telomeres, which correlate with several diseases of aging, including diabetes, cardiovascular disease, stroke, and cancer. Shortened telomeres might be both a cause and a consequence of chronic disease, although this has yet to be fully confirmed.
Disease Drivers of Aging: HIV, Diabetes, and Cancer
Chairs
Ronald Kohanski
National Institutes on Aging and Geroscience Interest Group, NIH
Steven Deeks
AIDS Research Institute; University of California, San Francisco
Claudia Gravekamp
Albert Einstein College of Medicine
Arti Hurria
City of Hope National Medical Center
Jeffrey Halter
University of Michigan
Kevin High
Wake Forest University
Nir Barzilai
Albert Einstein College of Medicine
Highlights
Each person has a unique fingerprint of chronic viral infections—HIV is one example.
HIV treatment normalizes some markers of aging.
Some manifestations of diabetes are relevant to aging, others are not.
Insulin resistance in the brain may accelerate age-related cognitive impairment.
Both cancer and cancer therapies promote cellular senescence and inflammation, which contribute to aging and disease.
Cancer treatment affects areas of the brain that are also changed by aging; these treatments can promote cognitive decline.
Aging with HIV
Despite the success of antiretroviral (ARV) therapy in improving health and increasing life span, people living with HIV are at an increased risk for many age-related diseases, such as cardiovascular disease, cancer, osteoporosis, liver disease, and cognitive impairment. Several panelists stressed the need for a multidimensional approach to investigate HIV and aging, saying that researchers should consider interactions between the seven pillars of aging described during the keynote presentations and focus on possible root causes driving aging.
Although the molecular pathways of aging in people living with HIV are well understood, the field lacks high-quality biomarkers to assess the effectiveness of interventions in clinical trials. The panelists advised aging researchers to make use of the large cohorts established in HIV, particularly MACS, WIHS, and VACS. Researchers have been following both infected and uninfected subjects in these cohorts for up to 30 years, and several types of samples, including serum, DNA, plasma, and urine, are available for study.
Many factors associated with HIV infection and treatment affect pathways involved in aging. (Image courtesy of Steven Deeks)
Gretchen Neigh of Virginia Commonwealth University discussed social stress and HIV. Her work in a rhesus monkey model, used to mimic human infection, showed that previous social stress increased the viral load of simian immunodeficiency virus (SIV) and delayed ARV response. The audience was curious as to whether this effect was attributable to the virus itself or to the illness that SIV causes. This question is difficult to answer in current animal models. Neigh added that the rhesus monkey model could be useful for studying the psychosocial aspects of HIV infection and for studying how social stressors affect viral reservoirs.
Beth Jamieson of the University of California, Los Angeles, showed that ARV therapy can partially normalize DNA methylation patterns, a hallmark of aging. She would like to explore this area further to find out how factors such as duration of infection and early treatment influence this effect. One attendee suggested targeting mitochondrial dysfunction to mitigate the effects of HIV on aging. The panelists pointed to the dearth of studies linking mitochondrial dysfunction to end-organ disease and noted that several older ARVs are mitochondrial toxins, complicating such analyses. Another area of investigation is infection of macrophages by HIV. While most of the panelists focused on infection of T cells, HIV infects macrophages during later stages of disease and could be a source of persistent inflammation.
The effects of type 2 diabetes on aging
It is difficult to establish which complications of type 2 diabetes accelerate age-related effects and which are specific to hyperglycemia, unrelated to aging. For example, patients with diabetes may experience vascular complications, such as neuropathy and nephropathy. However, these effects do not occur with normal aging and are likely a specific consequence of hyperglycemia. However, as Nir Barzilai of the Albert Einstein College of Medicine reminded attendees, researchers are not starting from scratch. Metformin, a common diabetes medication, also prevents several age-related diseases. Understanding this mechanism could be a starting point from which to investigate the effect of diabetes on age-related diseases.
Several audience members asked about the role of insulin resistance in the brain. During his presentation, C. Ronald Kahn of the Joslin Diabetes Center showed that knocking out the insulin receptor in the brain increased measures of anxiety in elderly mice but not in young mice. Kahn’s data also showed the importance of astroglia in insulin signaling. Attendees asked whether there were different families or subsets of astroglia in terms of insulin receptor expression or whether the cells had increased epigenetic variance with age. Kahn replied that he has not seen either effect, but added that he had not specifically looked for them.
One attendee questioned whether a homozygous knockout, which eliminates insulin signaling, is the best model for diabetes, noting that patients with diabetes retain some insulin signaling. Kahn replied that a heterozygous model may better recapitulate the biology of insulin resistance and that it may be worthwhile to use such a model.
There are many pathways and sites through which insulin resistance can affect aging in the brain. (Image courtesy of C. Ronald Kahn)
Another attendee asked about the use of CDK4 inhibitors, which are approved to treat some types of cancer. Jeffrey Halter of the University of Michigan showed that knocking out CDK4 in mice destroys β cells, which are responsible for producing insulin. Halter suggested that oncologists monitor for signs of β-cell dysfunction in patients taking CDK4 inhibitors for cancer. In addition, data from clinical trials of CDK4 inhibitors could be assessed retrospectively to evaluate whether these drugs have negative effects on β-cell function in humans.
One attendee asked the panel about the effects of asthma and decreased oxygen in obese people with diabetes and asthma. While no one on the panel has specifically investigated this relationship, the panelists cited studies in obese diabetics in which sleep apnea was shown to exacerbate insulin resistance. Improving sleep apnea decreased insulin resistance and diabetes.
Diabetes causes a subtle immunodeficiency. In other immunodeficiency models, such as HIV and transplant, cytomegalovirus (CMV) has been shown to play a role in driving vascular disease. One attendee postulated that CMV infection could be a good model to study the interaction between diabetes and aging in terms of vasculature, leukocytes, and endothelial function.
Premature aging caused by cancer and chemotherapy
Jan van Deursen of the Mayo Clinic explained that, in addition to apoptosis, chemotherapy can also induce cellular senescence in tumor cells. The panelists further explained that senescent tumor cells can be cleared by the immune system and that their ability to persist depends on the type of chemotherapy administered.
In patients with cancer, cellular senescence can occur as a consequence of normal aging or as a consequence of disease or treatment-related factors. (Image courtesy of Jan van Deursen)
Timothy Ahles of Memorial Sloan Kettering Cancer Center described how cancer and its treatment result in cognitive decline. One attendee remarked on how brain imaging in normal aging has evolved to not only monitor damage but also to look at compensatory mechanisms that may result from more serious brain damage. Ahles explained that cancer researchers have learned a lot from imaging studies of both normal aging and cognitive impairment because many of the systems affected by normal aging are also affected by cancer treatment. Wendy Demark-Wahnefried of the University of Alabama at Birmingham presented data on accelerated adverse body composition changes that occur as a result of cancer treatment, with chemotherapy inducing gains in fat and losses in muscle in the year following diagnosis that are comparable to 10 years of normal aging.
There are many good mouse models of cancer, but the disease is often studied in young animals, and studies using these models cannot investigate how aging affects cancer. The panelists noted that there has been a push in the research community to use models that develop cancers more slowly, and for researchers using models to induce cancer in older animals. However, achieving these goals can be difficult because it is time consuming and costly to maintain elderly animals. To defray some of these costs, the trans-NIH Geroscience Interest Group (GSIG) put out an RFA, joined by several other Institutes including NCI, to age animal models of disease. Funding for these research projects will be provided jointly by NIA and other relevant NIH institutes. The panelists encouraged researchers to look outside mouse models; a recent review described studies of naturally occurring cancers in pet dogs. The panelists also suggested studying cancer in nonhuman primates.
Several attendees asked about how to mitigate the effects of chemotherapy. Some patients undergo short-term fasting before chemotherapy, which has been shown to promote tumor shrinkage in mice. However, researchers have not studied whether this strategy promotes longevity, similar to the effect of dietary restriction in mice. Similarly, researchers have not systematically studied the effects of antidepressant use before chemotherapy, which has been shown to prevent negative cognitive outcomes of chemotherapy in animal models.
The panelists recommended early interventions, such as exercise during chemotherapy, to prevent or reverse decline in physical function in cancer patients. However, they also noted that later interventions can be effective. In the RENEW trial, an international sample of 641 older, long-term cancer survivors at least 5 years out from diagnosis who received materials and counseling on good dietary and exercise habits had a slower decrease in physical function than those who did not. In another initiative, cancer survivors paired with a gardener had healthier habits, improved function, and improved biomarkers of aging after one year of gardening.
The Way Forward
Moderator
Felipe Sierra
National Institute on Aging, NIH
Highlights
There is a need for a uniform definition of accelerated aging and standardized biomarkers to monitor aging.
Researchers should identify and focus on the root causes that drive aging instead of downstream effects.
Funding agencies should ensure that suitable aging-related experiments are included in grant proposals.
A call for uniformity
The meeting ended with a panel discussion on common themes and open research questions to advance therapies for chronic diseases and aging. Several attendees mentioned the need for a uniform definition of accelerated aging. There are many ways to define aging, ranging from molecular and cellular processes to functional ability and population age. In many animal models of aging, life span is the primary outcome for aging. However, this outcome would not be informative for clinicians; it does not reveal whether a patient is experiencing accelerated or normal aging or whether a treatment is improving the effects of aging. One attendee suggested creating an NIH toolbox of biological markers of aging to provide a common vocabulary for researchers. Currently, the best biomarkers of aging are composite measures that usually include function. The panelists recommended that studies measuring aging should include data representing at least two pillars of aging, such as DNA methylation and resistance to a stressor.
Several attendees also suggested that the research community create a single database, such as those housed at WikiPathways, to organize the biological pathways involved in aging and disease. Websites that currently house this information for aging do not include information on the relationships between aging and disease.
The big picture
Several panelists noted the importance of interactions between the seven pillars of aging. However, they cautioned against focusing on any single pillar and advised that the pillars be used as a guide and not as rigid categories for aging research. It is nonetheless clear that cellular senescence and inflammation are among the most important features of aging common to the three diseases discussed at this meeting. Cellular senescence has many forms, and targeting one form may not prevent others. Several attendees pointed out that therapeutic targeting of any one marker of inflammation or cellular senescence may not remedy their underlying cause(s) and their subsequent effects on aging and disease.
Funding and resources
The panelists also noted the need for more aging studies in general. One reason that investigators are hesitant to study aging is the time and expense of using aged animal models. While some larger centers, such as the Pepper Institute at Florida State University and the Shock Center at the University of Washington, have the infrastructure to do so, smaller institutions do not. Audience members recommended that the facilities at these centers be made available to researchers, particularly junior faculty, to help recruit more people to the aging field. The panelists also noted that datasets of relevance to aging are available on the NIA website.
Another reason for the lack of aging studies is the difficulty of acquiring funding for long-term, complex studies. The panelists remarked that grant reviewers sometimes ask that aging-related experiments be removed from proposals. Instead, aging experts on review committees should ensure that such complexity is included in proposals and confirm that an appropriate model system is being used so that studies on diseases that affect the elderly are not conducted in young mice. One audience member suggested supplements to existing grants be made available to fund extra samples for aging research. For example, ancillary studies could make use of specimens collected in clinical trials to analyze predictors of aging.
Open Questions
General
How can we best bring together those who study disease and those who study aging?
How should clinicians define aging and accelerated aging?
What biomarkers can be used to evaluate accelerated aging in the presence of chronic diseases and to assess the effects of interventions?
What are the best animal models to study accelerated aging in the presence of chronic disease?
Are life-extending therapies that work in animal models relevant to humans, and will they also extend health?
How can funding agencies, such as the NIA, encourage investigators to consider the effects of aging in their model systems?
Effects of HIV on aging
What is the role of senescent T cells in age-related diseases?
What can epigenetic changes in T cells tell us about the link between these cells and diseases of aging?
How does psychosocial stress affect HIV pathogenesis and response to treatment in humans?
What information can be gleaned from established HIV cohorts with respect to HIV and aging?
Future research questions for HIV and aging
How do disease factors, such as duration of infection and time of treatment, influence the effects of ARV therapy on markers of aging?
What can primate models of HIV infection tell us about psychosocial aspects of disease and how social stressors affect disease reservoirs?
What role might mitochondrial dysfunction play in HIV’s effect on aging?
How does infection of macrophages contribute to inflammation?
Effects of diabetes on aging
How do some diabetes therapies (eg, metformin and acarbose) increase longevity?
Which complications of diabetes are relevant to aging, and which are specific to increased blood glucose?
Could insulin resistance be a protective mechanism against accelerated aging?
Future research questions for diabetes and aging
How do CDK4 inhibitors affect β-cell function?
How do conditions that decrease the supply of oxygen, such as asthma and sleep apnea, influence insulin resistance?
What role might the immunodeficiency caused by diabetes play in driving vascular dysfunction?
Effects of cancer on aging
What are the different signs of, effects of, and treatments for cancer-related and chemotherapy-related senescence?
How can we definitively show that inflammation and coagulation affect function and survival?
Future research questions for cancer and aging
Can lifestyle changes improve cognitive function in older cancer patients?
How might short-term fasting prior to chemotherapy affect aging?
Can taking antidepressants before initiating chemotherapy mitigate cognitive decline?
The term “bioelectronic medicine” may seem to be more science fiction than medical reality, but this field of science has recently made significant strides in translating research from the lab to the clinic with promising results. From implantable devices to treat autoimmune diseases without medication to microchips to help quadriplegics regain movement, bioelectronic medicine is quickly moving into the forefront of scientific applications.
The premise of bioelectronic medicine is that nearly all cells in the human body are in some way regulated via information communicated from electrical signals from the nervous system. Similar to how implantable artificial pacemakers emit electrical impulses to regulate a heartbeat, various technologies have been developed to block, stimulate, or regulate the body’s neural signals to control the underlying molecular targets of many diseases.
Bioelectronic Medicine: A Viable Therapeutic Field
Bioelectronic medicine would not have emerged as a viable therapeutic field without the work of Kevin J. Tracey, MD, President and CEO of The Feinstein Institute for Medical Research-specifically, a key discovery in May of 1998. At the time it was believed that there was no communication between the nervous system and the immune system, but Tracey devised an experiment to test his own hypothesis on a link between the two systems.
Kevin J. Tracey, MD
Tracey predicted that stimulation of the vagus nerve with electrical impulses would reduce production of tumor necrosis factor (TNF), a cell signaling protein linked to inflammation. Electrical impulses were delivered to an exposed vagus nerve in a rat and after the cut was closed, Tracey administered endotoxin to trigger inflammation.
Seventy-five percent of TNF production was blocked, through activation of what Tracey coined as “the inflammatory reflex.” Since these research findings were published in Nature in 2000, Tracey has co-founded SetPoint Medical to develop an implantable device to stimulate the vagus nerve as a treatment for rheumatoid arthritis (RA) that is intended to last for 10 years. Results from a pilot study reported that patients with this implant experienced symptom improvements comparable to those taking medications for RA and a long-term study is currently underway.
A Chip Implanted in the Brain
Chad Bouton, also from The Feinstein Institute for Medical Research, was recently the lead author in a landmark study appearing in Nature on a neuroprosthetic device that, for the first time in a 24-year-old man with quadriplegia, allowed a paralyzed man to move his hand using only his brain. First, functional magnetic resonance imaging (fMRI) scans of Ian Burkhart’s brain were taken while he attempted to complete a range of hand movements; once Bouton and his team identified from the fMRI the areas of the motor cortex associated with the movement attempts, a chip was implanted in Burkhart’s brain.
This chip is designed to note the electrical activity from the motor cortex that is linked to movement and to transmit this information to a computer, which eventually translates these signals and sends them to a flexible sleeve on Burkhart’s arm. The result? Burkhart’s muscles were stimulated, and over time with training he has been able to make isolated finger movements and complete six different wrist and hand motions. There are limitations to the technology, as it can currently only be used in a laboratory for a limited amount of time and requires recalibration before each use.
Regardless, Burkhart sees great value in bioelectronic medicine. “Even if it’s something that I can never take home in my lifetime, I’m glad I’ve had the opportunity to take part in this study. I’ve had lots of fun with it. I know that I’ve done a lot of work to help other people as well,” Burkhart told Nature.
