To the Editor: We, the undersigned, are biotechnology executives, entrepreneurs, academic leaders and investors. We are gravely concerned about trends in the United States that are undermining our news media, such that more than 300 news publications across the country recently found it necessary to run coordinated editorials in defense of the First Amendment’s guarantee of freedom of the press.

Why do we, in particular, feel compelled to speak out? We dedicate our lives to discovering and developing new medicines. In recent years, we have witnessed astonishing advances in medicine, including treating diseases at the level of genes and cells. These modern miracles rely, more than anything else, on the free and public exchange of ideas. This encompasses the ability to collaborate, debate, and test one another’s ideas and findings, and to publish data regardless of political, religious or other external pressures or considerations. This is foundational to the scientific method, without which we all might still be living in caves and have an average life expectancy of 30.

The Framers of the US Constitution understood this well; in 1774, the First Continental Congress wrote, in the Appeal to the Inhabitants of Quebec:

The last right we shall mention regards the freedom of the press. The importance of this consists, besides the advancement of truth, science, morality, and arts in general, in … its ready communication of thoughts between subjects, and its consequential promotion of union among them, whereby oppressive officers are shamed or intimidated into more honorable and just modes of conducting affairs.

We believe it is critical to recognize that a free press is not equivalent to a perfect press. Reporters, just like scientists and every other variety of human being, at times make mistakes, can be biased, or may be just plain wrong. We see no compelling evidence to indicate that this is more prevalent now than it was 250 years ago at the time of our country’s founding, or any time thereafter.

The great virtue in having a free press is that everyone’s mistakes, including those of politicians, scientists and the press itself, have the opportunity to be exposed and ultimately corrected. Thomas Jefferson, who, like many presidents, chafed under the scrutiny of the press while he was in office, nevertheless wrote: “Our liberty depends on the freedom of the press, and that cannot be limited without being lost.” To consider our press “the enemy of the people” is antithetical to this key founding principle of our nation.

Technology now provides near instantaneous access to almost every vehicle for news; perversely, this has created more silos of news consumption, as we citizens receive news from outlets that are tailored to our particular tastes and prejudices, and we are less and less frequently exposed to alternative perspectives.

The progress of science and medicine requires that their practitioners not only be exposed to, but actively seek out, such perspectives. This is just as true for the progress of our country and our citizens at large. For America to remain the world’s foremost beacon of liberty and human progress, as well as the world’s leader in science and medicine, we must be resolute in upholding the rights guaranteed us by the First Amendment. 

ACKNOWLEDGMENTS

This letter represents solely the individual and personal views of the authors and signatories, and not those of their employers, companies, universities or any other organization or agency.

COMPETING INTERESTS

John Maraganore is CEO and board member of Alnylam Pharmaceuticals, and on the board of Agios Pharmaceuticals and the Biotechnology Innovation Organization. Steve Holtzman is president, CEO and board member of Decibel Therapeutics, and on the board of Molecular Partners. Ron Cohen is president and CEO of Acorda Therapeutics and a board member of VBL Therapeutics. Jeremy Levin is an officer at Ovid Therapeutics and on the board of Lundbeck A/S, Biocon Limited and ZappRX.

John M Maraganore¹, Steven Holtzman², Ron Cohen³& Jeremy M Levin⁴

Signatories to the statement

Michael Aberman⁵, Chris Adams⁶, Julian Adams⁷, Jeffrey Albers⁸, Bonnie Anderson⁹, Mara G Aspinall¹⁰, James E Audia¹¹, Martin Babler¹², David Baltimore¹³, Stephane Bancel¹⁴, Peter Barrett¹⁵, Zoe Barry¹⁶, David Bartel¹⁷, Jean-Jacques Bienaime¹⁸, Burkhard Blank¹⁹, Robert I Blum²⁰, Daniel M Bradbury²¹, Eugene Braunwald²², John P Butler²³, Bruce Carter²⁴, Gustav Christensen²⁵, Isaac Ciechanover²⁶, Chip Clark²⁷, John K Clarke²⁸, Michael D Clayman²⁹, Jeffrey L Cleland³⁰, David Clem³¹, N Anthony Coles³², Charles L Cooney³³, Robert K Coughlin³⁴, Zoltan Csimma³⁵, Sally J Curley³⁶, Bassil Dahiyat³⁷, Daniel A de Boer³⁸, Elisabet de los Pinos³⁹, Ronald A DePinho⁴⁰, Douglas Doerfler⁴¹, Daniel Dornbusch⁴², Richard H Douglas⁴³, Deborah Dunsire⁴⁴, Neil Exter⁴⁵, Nima Farzan⁴⁶, Jean-François Formela⁴⁷, Robert Forrester⁴⁸, Maureen N Franco⁴⁹, Cedric Francois⁵⁰, Heather Franklin⁵¹, Scott Garland⁵², Simba Gill⁵³, David V Goeddel⁵⁴, Maxine Gowen⁵⁵, Kurt Graves⁵⁶, Mary Ann Gray⁵⁷, Barry Greene⁵⁸, David-Alexandre C Gros⁵⁹, Faheem Hasnain⁶⁰, Michael Hammerschmidt⁶¹, Elma S Hawkins⁶², Russell Herndon⁶³, Paul Hastings⁶⁴, Andrew Hindman⁶⁵, Annalisa Jenkins⁶⁶, Cigall Kadoch⁶⁷, Emil D Kakkis⁶⁸, Johanne Kaplan⁶⁹, Laurie Keating⁷⁰, Rachel King⁷¹, Vanessa King⁷², Scott Koenig⁷³, Peter Kolchinsky⁷⁴, Daphne Koller⁷⁵, Marc Kozin⁷⁶, Paul Laikind⁷⁷, Robert Langer⁷⁸, Donna L LaVoie⁷⁹, John J Lee⁸⁰, Jonathan Leff⁸¹, Alan Levy⁸², Judy Lieberman⁸³, Christine Lindenboom⁸⁴, David R Liu⁸⁵, Uri Lopatin⁸⁶, Ted W Love⁸⁷, David N Low Jr⁸⁸, Nagesh K Mahanthappa⁸⁹, Tony Martignetti⁹⁰, W Eddie Martucci⁹¹, Kiran Mazumdar-Shaw⁹², Tracey L McCain⁹³, Corey M McCann⁹⁴, David J McLachlan⁹⁵, David Meeker⁹⁶, Ravi Mehrotra⁹⁷, Steven J Mento⁹⁸, Rachel Meyers⁹⁹, Gregory Miller¹⁰⁰, Ken Mills¹⁰¹, Kenneth I Moch¹⁰², Michael M Morrissey¹⁰³, Robert Mulroy¹⁰⁴, Imran Nasrullah¹⁰⁵, William J Newell¹⁰⁶, John F Neylan¹⁰⁷, Bernat Olle¹⁰⁸, Eric T Olson¹⁰⁹, Douglas E Onsi¹¹⁰, John E Osborn¹¹¹, Julia C Owens¹¹², Stelios Papadopoulos¹¹³, Steve Paul¹¹⁴, Brian J G Pereira¹¹⁵, Doris Peterkin¹¹⁶, Cary Pfeffer¹¹⁷, Mark Pruzanski¹¹⁸, Gerald E Quirk¹¹⁹, Michael Raab¹²⁰, Paula Ragan¹²¹, Amit Rakhit¹²², Bill Rastetter¹²³, Ron Renaud¹²⁴, Jason P Rhodes¹²⁵, Scott M Rocklage¹²⁶, Michael Rosenblatt¹²⁷, William J Rutter¹²⁸, Camille Samuels¹²⁹, James Sapirstein¹³⁰, Amar Sawhney¹³¹, David Scadden¹³², George Scangos¹³³, John A Scarlett¹³⁴, Stuart L Schreiber¹³⁵, Paul J Sekhri¹³⁶, Eric Shaff¹³⁷, Bennett Shapiro¹³⁸, Thomas Shenk¹³⁹, Nancy Simonian¹⁴⁰, William Slattery¹⁴¹, Erika R Smith¹⁴², Bruce Steel¹⁴³, Harald F Stock¹⁴⁴, Clifford J Stocks¹⁴⁵, Michael Su¹⁴⁶, Tim Surgenor¹⁴⁷, Jean-Christophe Tellier¹⁴⁸, Charles Theuer¹⁴⁹, Martin Tolar¹⁵⁰, Eric Topol¹⁵¹, Beth Trehu¹⁵², Akshay K Vaishnaw¹⁵³, Christi van Heek¹⁵⁴, Michael J Vasconcelles¹⁵⁵, George P Vlasuk¹⁵⁶, Michel Vounatsos¹⁵⁷, Christopher T Walsh¹⁵⁸, Jane Wasman¹⁵⁹, Andrew Weisenfeld¹⁶⁰, Yaron Werber¹⁶¹, Christoph Westphal¹⁶², Wendell Wierenga¹⁶³, Terry Winters¹⁶⁴, Eugene Williams¹⁶⁵, Chuck Wilson¹⁶⁶, Peter Wirth¹⁶⁷, Kleanthis Xanthopoulos¹⁶⁸ & Sanford (Sandy) Zweifach¹⁶⁹

¹Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts, USA. ²Decibel Therapeutics, Boston, Massachusetts, USA. ³Acorda Therapeutics, Ardsley, New York, US. ⁴New Milford, Connecticut, USA. ⁵Quentis Therapeutics, Inc., New York, New York, USA. ⁶Cydan II, Cambridge, Massachusetts, USA. ⁷Gamida Cell, Boston, Massachusetts, USA. ⁸Blueprint Medicines, Cambridge, Massachusetts, USA. ⁹Veracyte, Inc., South San Francisco, California, USA. ¹⁰Health Catalysts Group, Tucson, Arizona, USA. ¹¹Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts, USA. ¹²Principa Biopharma, South San Francisco, California, USA. ¹³Caltech, Pasadena, California, USA. ¹⁴Moderna, Inc., Cambridge, Massachusetts, USA.  ¹⁵Atlas Venture, Cambridge, Massachusetts, USA. ¹⁶ZappRx, Boston, Massachusetts, USA. ¹⁷MIT/Whitehead Institute, Cambridge, Massachusetts, USA. ¹⁸BioMarin Pharmaceutical, Novato, California, USA. ¹⁹Acorda Therapeutics, Inc., Ardsley, New York, USA. ²⁰Cytokinetics, Inc., South San Francisco, California, USA. ²¹Equillium, Inc., La Jolla, California, USA. ²²Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, USA. ²³Akebia Therapeutics, Cambridge, Massachusetts, USA. ²⁴Novo Nordisk (retired), Seattle, Washington, USA. ²⁵Morphic Therapeutic, Waltham, Massachusetts, USA. ²⁶Atara Biotherapeutics, South San Francisco, California, USA. ²⁷Genocea Biosciences, Inc., Cambridge, Massachusetts, USA. ²⁸Cardinal Partners, Princeton, New Jersey, USA. ²⁹Flexion Therapeutics, Burlington, Massachusetts, USA. ³⁰Graybug Vision, Redwood City, California, USA. ³¹Lyme Properties 2, LLC, West Lebanon, New Hampshire, USA. ³²Yumanity Therapeutics, Cambridge, Massachusetts, USA. ³³Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. ³⁴MassBio, Cambridge, Massachusetts, USA. ³⁵Csimma LLC, Lincoln, Massachusetts, USA. ³⁶IRC, CGIR, LLC, Savannah, Georgia, USA. ³⁷Xencor, Monrovia California, USA. ³⁸ProQR Therapeutics, Cambridge, Massachusetts, USA. ³⁹Aura Biosciences Inc., Cambridge Massachusetts, USA. ⁴⁰Department of Cancer Biology, MD Anderson Cancer Center, Houston, Texas, USA. ⁴¹MaxCyte Inc., Gaithersburg Maryland, USA. ⁴²Dornbusch & Company, Oakland, California, USA. ⁴³Aldeyra Therapeutics, Lexington, Massachusetts, USA. ⁴⁴Lundbeck Pharmaceuticals, København, Denmark. ⁴⁵Third Rock Ventures, Boston, Massachusetts, USA. ⁴⁶PaxVax, Redwood City, California, USA. ⁴⁷Atlas Venture, Cambridge, Massachusetts, USA. ⁴⁸Verastem, Inc., Needham, Massachusetts, USA. ⁴⁹Cambridge BioMarketing, Boston, Massachusetts, USA.  ⁵⁰Apellis Pharmaceuticals, Crestwood, Kentucky, USA. ⁵¹Blaze Bioscience Inc., Seattle, Washington, USA. ⁵²Relypsa, a Vifor Pharma Group Company, Redwood City, California, USA.  ⁵³Evelo Biosciences, Boston, Massachusetts, USA. ⁵⁴The Column Group, San Francisco, California, USA. ⁵⁵Trevena Inc., Wayne, Pennsylvania, USA. ⁵⁶Intarcia Therapeutics, Boston, Massachusetts, USA. ⁵⁷Gray Strategic Advisors, LLC, New York, New York, USA. ⁵⁸Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. ⁵⁹Imbria Pharmaceuticals, Rancho Santa Fe, California, USA. ⁶⁰Gossamer Bio, San Diego California, USA. ⁶¹Science History Institute, Philadelphia, Pennsylvania, USA. ⁶²Redpin Therapeutics, New York, New York, USA. ⁶³Hydra Biosciences, Cambridge, Massachusetts, USA. ⁶⁴Nkarta Therapeutics, South San Francisco, California, USA. ⁶⁵Acorda Therapeutics, Ardsley, New York, USA. ⁶⁶Cell Medica, London, UK. ⁶⁷Dana-Farber Cancer Institute/Harvard Medical School/MIT/Foghorn Therapeutics, Inc., Boston, Massachusetts, USA. ⁶⁸Ultragenyx Pharmaceutical Inc., Novato, California, USA. ⁶⁹ProMIS Neurosciences, Cambridge, Massachusetts, USA.  ⁷⁰Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts, USA. ⁷¹GlycoMimetics, Rockville, Maryland, USA. ⁷²Virion Biotherapeutics LLC, London, UK. ⁷³MacroGenics Inc., Rockville, Maryland, USA. ⁷⁴RA Capital Management, Boston, Massachusetts, USA. ⁷⁵Insitro, South San Francisco, California, USA. ⁷⁶Naples, Florida, USA. ⁷⁷ViaCyte, San Diego, California, USA. ⁷⁸MIT, Cambridge, Massachusetts, USA. ⁷⁹LaVoieHealthScience, Boston, Massachusetts, USA. ⁸⁰Decibel Therapeutics, Boston, Massachusetts, USA. ⁸¹Deerfield Management, New York, New York, USA. ⁸²Tasso, Inc., Bellevue, Washington, USA. ⁸³Harvard Medical School, Boston, Massachusetts, USA. ⁸⁴Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. ⁸⁵Broad Institute/Howard Hughes Medical Institute/Harvard University, Cambridge, Massachusetts, USA. ⁸⁶Assembly Biosciences, San Francisco, California, USA. ⁸⁷Global Blood Therapeutics, South San Francisco, California, USA. ⁸⁸MTS Health Partners, New York, New York, USA. ⁸⁹Scholar Rock, Cambridge, Massachusetts, USA. ⁹⁰Inspired Purpose Coaching LLC, Canton, Massachusetts, USA. ⁹¹Akili Interactive Labs, Inc., Boston, Massachusetts, USA. ⁹²Biocon Pharma Inc., Iselin, New Jersey, USA.  ⁹³Blueprint Medicines Corporation, Cambridge, Massachusetts, USA. ⁹⁴Pear Therapeutics, Boston, Massachusetts, USA. ⁹⁵Skyworks Solutions, Inc., Woburn, Massachusetts, USA. ⁹⁶KSQ Therapeutics, Cambridge Massachusetts, USA.  ⁹⁷MTS Health Partners, New York, New York, USA. ⁹⁸Conatus Pharmaceuticals Inc., San Diego, California, USA. ⁹⁹Third Rock Ventures, Boston, Massachusetts, USA. ¹⁰⁰Visterra Inc., Waltham, Massachusetts, USA. ¹⁰¹Regenxbio Inc., Rockville, Maryland, USA. ¹⁰²Cognition Therapeutics, Inc., Pittsburgh, Pennsylvania, USA. ¹⁰³Exelixis, Inc., Alameda, California, USA.   ¹⁰⁴PTX Partner Therapeutics, Lexington, Massachusetts, USA. ¹⁰⁵Boehringer Ingelheim Pharmaceuticals, Cambridge, Massachusetts, USA. ¹⁰⁶Sutro Biopharma, Inc., South San Francisco, California, USA. ¹⁰⁷Keryx Biopharmaceuticals, Inc., Boston, Massachusetts, USA. ¹⁰⁸Vedanta Biosciences, Cambridge, Massachusetts, USA. ¹⁰⁹Marblehead, Massachusetts, USA. ¹¹⁰HealthCare Ventures, Cambridge, Massachusetts, USA. ¹¹¹BioVentures/Egalet Corporation, Wayne, Pennsylvania, USA. ¹¹²Millendo Therapeutics, Inc., Ann Arbor, Michigan, USA. ¹¹³Biogen Inc., Cambridge Massachusetts, USA.  ¹¹⁴Karuna Pharmaceuticals, Boston, Massachusetts, USA. ¹¹⁵Visterra, Inc., Cambridge, Massachusetts, USA. ¹¹⁶OncoPep, Inc., North Andover Massachusetts, USA. ¹¹⁷Third Rock Ventures, Boston, Massachusetts, USA. ¹¹⁸Intercept, New York, New York, USA. ¹¹⁹Syros Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.  ¹²⁰Ardelyx, Inc., Fremont, California, USA. ¹²¹X4 Pharmaceuticals Inc., Cambridge, Massachusetts, USA. ¹²²Ovid Therapeutics, New York, New York, USA. ¹²³Grail/Neurocrine Biosciences/Fate Therapeutics/Daré Bioscience/Regulus Therapeutics, Rancho Santa Fe, California, USA. ¹²⁴Translate Bio, Lexington, Massachusetts, USA. ¹²⁵Atlas Venture, Cambridge, Massachusetts, USA. ¹²⁶5AM Ventures, Boston, Massachusetts, USA. ¹²⁷Flagship Pioneering, Cambridge, Massachusetts, USA. ¹²⁸Synergenics, LLC., San Francisco, California, USA. ¹²⁹Venrock, Palo Alto, California, USA. ¹³⁰Contravir Pharmaceuticals, Edison, New Jersey, USA. ¹³¹Ocular Therapeutix, Bedford, Massachusetts, USA. ¹³²Harvard University/Massachusetts General Hospital, Boston, Massachusetts, USA. ¹³³Vir Biotechnology, Inc., San Francisco, California, USA. ¹³⁴Geron Corporation, Menlo Park, California, USA. ¹³⁵Broad Institute/Harvard University, Boston, Massachusetts, USA. ¹³⁶Lycera Corp., New York, New York, USA. ¹³⁷Seres Therapeutics, Cambridge Massachusetts, USA. ¹³⁸Puretech Health, Boston, Massachusetts, USA. ¹³⁹Princeton University, Princeton, New Jersey, USA. ¹⁴⁰Syros Pharmaceuticals, Cambridge Massachusetts, USA. ¹⁴¹Deerfield Management, New York, New York, USA. ¹⁴²ReNetX Bio, New Haven, Connecticut, USA.  ¹⁴³Equillium, Inc., La Jolla California, USA. ¹⁴⁴CognifiSense, Inc., Park City, Utah, USA. ¹⁴⁵OncoResponse, Inc., Seattle, Washington, USA.  ¹⁴⁶Decibel Therapeutics Incorporated, Boston, Massachusetts, USA. ¹⁴⁷Red Sky Partners, Cambridge, Massachusetts, USA. ¹⁴⁸UCB S.A., Brussels, Belgium. ¹⁴⁹Tracon Pharmaceuticals Inc., San Diego, California, USA. ¹⁵⁰Alzheon, Framingham, Massachusetts, USA.  ¹⁵¹Scripps Research Translational Institute/Molecular Medicine, La Jolla, California, USA. ¹⁵²Jounce Therapeutics, Inc., Cambridge, Massachusetts, USA.  ¹⁵³Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts, USA.  ¹⁵⁴Bio Point Group, Punta Gorda, Florida, USA. ¹⁵⁵Unum Therapeutics Inc., Cambridge, Massachusetts, USA. ¹⁵⁶Navitor Pharmaceuticals, Inc., Cambridge, Massachusetts, USA. ¹⁵⁷Biogen, Cambridge, Massachusetts, USA. ¹⁵⁸ChEM-H Institute/Stanford University, Stanford, California, USA.  ¹⁵⁹Acorda Therapeutics, Inc., Ardsley, New York, USA. ¹⁶⁰MTS Health Partners LP, New York, New York, USA. ¹⁶¹Ovid Therapeutics, New York, New York, USA. ¹⁶²TScan Therapeutics, Boston Massachusetts, USA. ¹⁶³Crinetics Pharmaceuticals, San Diego, California, USA. ¹⁶⁴Scottsdale, Arizona, USA. ¹⁶⁵ProMIS Neurosciences, Cambridge, Massachusetts, USA. ¹⁶⁶Unum Therapeutics Inc., Cambridge, Massachusetts, USA. ¹⁶⁷Syros Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.  ¹⁶⁸Irras, San Diego, California, USA. ¹⁶⁹Nuvelution Pharma, Inc., South San Francisco, California, USA.

Emily Whitehead, 12, the first child to receive CAR-T cell therapy has been cancer-free for five years. {credit}Getty Images{/credit}

On July 12, in a historic move, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 10–0 in favor of approving CTL019 (tisagenlecleucel), a CD19-targeting chimeric antigen receptor (CAR) T-cell therapy developed by Novartis for treating relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in children and young adults. The committee’s unanimous backing opens the door to approval of the therapy by the US Food and Drug Administration (FDA) on or before October 3. The US, which has lagged behind Europe in approving both gene therapy and cell therapy, has now taken a lead in adopting an innovative immuno-oncology treatment that combines elements of each modality—and which addresses a real and sizeable unmet need. “It reflects the culmination of many decades of work in several discrete areas, which all came together to help patients,” says Glenn Dranoff, global head of immuno-oncology at Novartis Institutes for BioMedical Research in Boston, which developed the therapy in partnership with Carl June at the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia. A new era of high-tech medicine is about to begin.

The case for CTL019’s approval is persuasive. Its dramatic efficacy—an 82.5% overall response rate in a pivotal program treating highly refractory patients and a 79% survival probability over 12 months—combined with an apparently manageable safety profile, makes the agency’s go-ahead a formality. The arguments in favor of approval are made even more compelling by the limited treatments for the approximately 15% of pediatric ALL patients who relapse after high-dose chemotherapy. Their only option, a hematopoietic stem cell transplant, is potentially curative but remains a high risk. Will CAR-T therapy will be a bridge to, or, ultimately, a replacement for, transplant? “Obviously, we all sure hope it’s a replacement for it,” says Timothy Cripe, professor of pediatrics at The Ohio State University in Columbus, Ohio, and a member of the ODAC panel.

Once it is approved, Basel, Switzerland–based Novartis plans to restrict the initial roll-out of CTL019 to 30–35 accredited treatment centers in the US, all of which will be trained on a comprehensive risk-mitigation strategy that drew high praise from several ODAC members during the hearing. Novartis will provide training to transplant teams on managing cytokine release syndrome (CRS)—which occurred in 81% of patients treated in its pivotal program—and neurotoxicities associated with CTL019 therapy. An authorized Novartis representative will be on site to monitor performance and compliance and to ensure that the correct systems are in place to ensure that only accredited personnel can prescribe CTL019. Depending on the experience gained with CTL019 during the first six to twelve months after approval, the therapy may then be rolled out to additional centers, says David Lebwohl, CAR-T franchise global program head at Novartis.

The geographic spread could be wider, says Cripe, who pointed out during the hearing that the limited rollout could place an emotional and financial burden on families who are not located close to one of the first wave of designated treatment centers. “There are 175 bone marrow transplant centers in the US certified by the US bone marrow registry that have to reach certain standards,” he says. It’s a measure of his confidence within the clinical community that he considers the severe side effects that accompany CAR-T cell therapy to be manageable. “The benefit seems to be so dramatic, it’s worth the risk,” Cripe says. Hematologists, moreover, are accustomed to managing the multi-organ side effects that often accompany allogeneic hematopoietic stem cell transplantation. What’s new is the five-step CRS treatment algorithm, which Novartis developed with the help of clinical collaborator Stephan Grupp, of the Children’s Hospital of Philadelphia.

Although CRS is an on-target effect—the most severe cases are associated with high levels of disease burden—it can be fatal. Grupp’s key observation was that Genentech’s anti-IL-6 antibody Actemra (tocilizumab) is an effective tool in controlling CRS. Only 6% of patients required fourth-line CRS management therapy during the Novartis pivotal program; none required fifth-line treatment. “There were no cases of cerebral edema in this study,” says Grubb. It’s one of the key risks associated with CRS and has dogged the other leaders in the development of CD19-targeted CAR-T cell therapies, namely, Kite Pharma, of Santa Monica, California, and Juno Therapeutics, of Seattle, Washington (Nat. Biotechnol. 35, 492, 2017).

Still, some questions about CTL019’s mechanism and side effects remain unanswered. The causes of the neurotoxicities that accompany CAR-T cell therapy are not fully understood; why a minority of patients do not respond to therapy is not understood either. The dose levels Novartis used in the pivotal study did not appear to correlate with either response, CRS severity or other safety signals, such as neurotoxicity or cytopenia. Novartis has not disclosed the release specifications for CTL019 infusions, but each contains mixed populations of both transduced and non-transduced T cells, representing various T-cell subsets. CTL019 is a living biologic, noted FDA reviewer Xiaobin Victor Lu during the advisory panel hearing. “The T cells in the product can expand and differentiate during the manufacturing process and after administration to patients,” he says. The heterogeneity of the infusions does not seem to compromise the efficacy of the therapy, but several advisory committee members questioned the associated safety implications. “This is one area which could really affect the future of this therapy,” says Larry Kwak, professor in translational medicine at City of Hope, Duarte, California. These questions are likely to stimulate further clinical research, says Dranoff. In addition, Novartis plans to conduct a follow-up study of at least 15 years’ duration, in which patients will be monitored for adverse events, efficacy, immunogenicity, CD19 CAR transgene persistence, the emergence of replication-competent lentivirus, and secondary malignancies associated with insertional mutagenesis.

Dranoff identifies three immediate priorities for Novartis in terms of further optimization of CTL019: simplifying the manufacturing process to enable it to scale up to meet the needs of more patients; extending the therapy to other B-cell malignancies; and extending it to other cancers, including solid tumors. Novartis has already reduced the rate of manufacturing failure, from insufficient expansion of a patient’s T cells, from 9% in the pivotal program to about 2% in recent lots. At commercial rollout, the turnaround time between receiving patients’ cells and infusion of the modified end product will be 22 days, one week less than the average time in the pivotal program. Further process improvements are also underway at Oxford Biomedica, an Oxford, UK–based gene therapy firm, which supplies the recombinant lentiviral vector encoding the CAR components used in CTL019. These include the extracellular CD19-targeting murine single-chain fragment antibody, spacer and transmembrane domains derived from human CD8-α, a human intracellular 4-1BB (CD137) co-stimulatory domain and a human intracellular CD3ζ T-cell-activation domain. The vector for CTL019 is currently produced with Oxford’s ‘cell factory’ process, a two-dimensional, multi-tray system, but its next-generation platform involves a 200-liter bioreactor. This could provide a tenfold reduction in price “We’re working hard with Novartis to move to the bioreactor process,” says CEO John Dawson. Oxford and Novartis, whose relationship extends back to 2013, recently entered a new three-year supply deal, covering CTL019 and other undisclosed CAR-T cell therapies, which could be worth over $100 million to the UK firm. It will also receive low-single-digit royalties on sales of CTL019 and other CAR-T products.

Looking ahead, Novartis, is gearing up for a filing later this year in diffuse large B-cell lymphoma and is also testing CTL019 in multiple myeloma and, in combination with the Bruton’s tyrosine kinase inhibitor Imbruvica (ibrutinib), in chronic lymphocytic leukemia. (The latter drug is jointly marketed by AbbVie, of North Chicago, Illinois, and Johnson & Johnson, of New Brunswick, New Jersey.)

But it is unclear at this point how broadly the CAR-T concept can be extended. CAR-T cell therapies that target other tumor antigens, particularly those expressed on solid tumors, have lagged behind CD19-directed therapies (Nat. Biotechnol. 34, 1079–1081, 2016). “Have we developed a new treatment for B-cell malignancies or is this a new paradigm for cancer in general?” asks Renjer Brentjens, medical oncologist at Memorial Sloan Kettering Cancer Center in New York and scientific co-founder of Juno Therapeutics. “It not a coincidence, I think, that everyone started targeting CD19.” Finding other tumor-associated antigens that are not expressed on essential tissue is challenging. “This becomes particularly difficult in the area of solid tumor malignancies,” Brentjens says. Patterns of antigen expression on solid tumor cells are more heterogeneous than those on hematological cancer cells, he says. “Immune escape is extremely possible,” he says. The immunosuppressive ‘scaffold’ that solid tumors erect further complicates the picture. “I do think the technology, as it stands right now—I may be wrong—is most likely going to be restricted to a select number of malignancies,” he says.  However, novel CAR-T architectures incorporating additional immunostimulatory features, as well as molecular safety switches, are already in early stages of development. A first CAR-T cell approval this year is likely to energize this research.

The pioneers who brought the technology to its present juncture deserve credit for keeping faith with the concept that the T-cell response is programmable, at least in the sense that the set of biological instructions encoded in an infusion of CAR-T cells can, when its technical specifications are properly defined and the clinical context in which it is deployed is properly understood, lead to dramatic outcomes. Young patients with relapsed or refractory B-cell ALL will be the first to benefit from this innovation; they’re unlikely to be the last. “We need to pause and acknowledge the extraordinary amount of scientific learning that went into this event,” Dranoff says.

Cormac Sheridan, Dublin

Jennifer Doudna speaks about CRISPR editing at the World Economic Forum, at Davos, Switzerland in January. Source: Michele Limina/Photoshot/Newscom

The organizers of a recent meeting in Napa, California, to consider the broad societal implications of clustered, regularly interspaced, short palindromic repeats (CRISPR) genome editing have succeeded in their primary goal of stimulating public debate on the ethical issues raised by the technology. Although the event, held on January 24, took place behind closed doors, a subsequent commentary from its leading participants—plus two influential non-attendees, George Church of Harvard Medical School in Boston, and Martin Jinek of the University of Zurich—prompted widespread media coverage (Science 348, 36–38, 2015). The group has called for a broadly based discussion of the potential merits and risks of the technology and a global moratorium on germline applications, until such time, if ever, responsible uses can be identified.

But the declaration, along with a high-profile commentary in The Wall Street Journal on April 9 from David Baltimore and Paul Berg, two veterans of the 1970s debates on genetic engineering, has already altered the social context in which new developments in the field will be received. Any scientist or organization that crosses the ethical Rubicon by conducting human germline engineering experiments will now face a considerable level of opprobrium. “I doubt the unsanctioned use will happen soon,” says Nobel laureate Craig Mello of the University of Massachusetts Medical School, in Worcester, and a scientific founder of Basel-based CRISPR Therapeutics. “It’s not something that’s going to be easy, cost-effective or safe, given existing technology.”

The Napa event was by no means representative of all the main players in CRISPR-Cas9, however, which leaves its main organizer, the Innovative Genomics Initiative at the University of California, Berkeley, open to criticism that it is attempting to set the agenda without first building a broad front within the scientific community and beyond. “I do think it’s a discussion the community should have—not just the West Coast community,” says Rodger Novak, CEO and co-founder CRISPR Therapeutics, whose scientific founder, Emmanuelle Charpentier, is, along with Berkeley’s Jennifer Doudna, co-inventor of the technology. At the same time, there is no evidence of a rift opening up between those who attended and those who did not. “I don’t feel slighted in any way,” says Mello. “Anything that raises awareness is important.”

The cluster of companies working with CRISPR-Cas9 shares a common goal in ensuring that the technology gains public and regulatory acceptance and avoids the kind of backlash that would halt its development. All of them are proceeding cautiously. “The promise is so exciting, nobody wants to take the step that would undermine that promise,” says Katrine Bosley, CEO of Cambridge, Massachusetts–based Editas Medicine. Although individual companies are keeping details of their development programs under wraps for now, the present focus is on therapies that target somatic cells, most likely in ex vivo settings initially. “Germline, from an industry perspective right now, is a no,” says Novak. Nessan Bermingham, CEO of Cambridge-based Intellia Therapeutics, echoes the point. “We are not doing any germline modification—it is not in our business plan, nor is there any [such] plan at all.” Clinical trials involving therapies based on CRISPR-Cas9 have not yet started, but the research effort is moving ahead quickly. “I would be disappointed if we didn’t see something in the clinic three years from now,” says Novak. It could happen even sooner.

Whether CRISPR-Cas9 should be singled out for special attention is open to debate. It is not the first genome editing technology to emerge. Meganucleases, zinc finger nucleases (ZFNs) and transcription activator–like effector nucleases (TALENs) all preceded it. Sangamo Biosciences, of Richmond, California, is conducting trials of a ZFN-based therapy in HIV patients at present. What’s more, together with other researchers, Ed Lanphier and Fyodor Urnov from Sangamo authored a Comment in Nature (Nature 519, 410-411, 2015) calling for a moratorium on genome editing of the human germline. What distinguishes CRISPR-Cas9 from the earlier technologies is its accessibility, its ease of use and its low cost. Germline engineering with the technology, although not trivial, is feasible in a well-equipped molecular biology laboratory. “Something that was pretty much theoretical before now is now facing us,” says Bosley.

Policing the use of the technology is practically impossible. “One cannot control what’s happening in China, for example,” says Intellia’s Bermingham. Rumors are swirling through the research community that at least one laboratory may already have conducted human germline experiments—and that papers describing the process have been submitted to journals or published.

André Choulika, CEO and founder of Paris-based genome editing firm Cellectis is not convinced that the advent of CRISPR-Cas9 creates any new problems, however. “CRISPR is essentially a revolution because it makes gene editing accessible to any researcher—that’s all,” he says. Cellectis plans to complete an investigational new drug filing this year of allogeneic chimeric antigen receptor T-cells engineered using TALENs. “I think you could do germline changes with zinc finger nucleases, TALENs or meganucleases,” he says. The current explosive uptake of CRISPR-Cas9 in academic laboratories will not necessarily be replicated in clinical settings, he argues. “Once you want to push the technology into therapeutic applications—you want to be super-specific, you don’t want off-target effects—then it becomes far more challenging.” Ethical discussions, he suggests, are best left to those who are qualified to engage in them. “We are scientists, not philosophers.”

The Napa meeting has obvious resonances with the historic 1975 Asilomar conference on recombinant DNA, which set the agenda for managing the then poorly understood risks associated with genetic engineering. Paul Berg from Stanford University and David Baltimore, at Caltech in Pasadena, embodied that link by attending the Napa meeting and lending their names to the present campaign to prevent germline experiments. Science historian Susan Wright, who is currently based at the University of California, Santa Cruz, is author of Molecular Politics (Univ. of Chicago Press, 1994), a detailed account of the development of genetic engineering policy in the US and the UK. She is critical of any interpretation of the stance taken at the Asilomar meeting as “a noble act of self-sacrifice.” Its real focus, she says, was to shape consensus around how the technology would be used.

Forty years on, industry interests are more powerful, but the ethical stakes are higher than ever, and the uncertainty surrounding the long-term applications of the technology is genuine. The prospect of rogue laboratories operating in unregulated jurisdictions is not difficult to imagine. “We live in a world where female fetuses are routinely aborted, because the societies where that happens place a higher value on males,” says Ron Cohen, CEO of Acorda Therapeutics, of Ardsley, New York, and vice chair of the Biotechnology Industry Organization of Washington, DC (BIO)’s health section, who stresses he was speaking in a personal capacity. BIO is still formulating a policy on the area. For now, it states that “it is imperative” that the scientific community joins in an “open public discourse” to consider the responsible use of the technology.

In the meantime, the companies that are actively engaged with the technology have their hands full of routine work focused on establishing the safety profile of the technology in noncontroversial settings. “A large part of the work that’s been done has been documenting how frequently the off-target events occur,” Mello says. Different ways of monitoring and minimizing these events have started to emerge, not all of which have been published as yet. “I’m aware of several that are promising,” Mello says.

In the long term though, there is a possibility of germline applications (Box 1).  “Would it be unethical not to fix something if you could?” he asks. “If it were very safe, wouldn’t it be wrong not to?” But it will take a very long time—and significant research on CRISPR-Cas9 and on disease biology—to be in a position even to contemplate those questions.

Cormac Sheridan, Dublin

Box 1. OvaScience IVF offerings stuck in regulatory limbo

Some companies working on infertility treatments have already started combining their platforms with genome engineering approaches. In December 2013, OvaScience a Cambridge, Massachusetts–based biotech working on next-generation in vitro fertilization technologies formed a joint venture with synthetic biology company Intrexon of Germantown, Maryland. Under the OvaXon Joint Venture the companies agreed to combine OvaScience’s EggPC (egg precursor cells: immature egg cells found inside the protective ovarian lining) platform with Intrexons’s genome engineering capabilities to prevent inherited diseases in humans, such as mitochondrial and other genetic disorders.

In its advertised offerings for fertility clinics, OvaScience is not employing CRISPR-Cas9—or any other form of genetic engineering—at present. Even so, the company has hit regulatory barriers in its efforts to translate controversial new insights on oocyte biology into fertility treatments.

The company was founded in 2011 to commercialize the research of co-founder Jonathan Tilly, then of Harvard Medical School, who is now chair of the biology department at Northeastern University in Boston. Over a decade ago, Tilly and colleagues identified putative immature egg precursor cells in the ovaries of juvenile and adult mice, a finding at odds with a central dogma of mammalian biology—that the supply of eggs is fixed at birth. (Nature 428, 145–150, 2004). The science remains disputed, but Tilly’s group and others have since reported the same observations in humans (Reprod. Sci. 20, 7–15, 2013). Moreover, OvaScience plans to roll out a treatment based on this concept to women undergoing in vitro fertilization (IVF) later this year. It aims to boost women’s egg reserves by transferring egg precursors—oogonial stem cells—from the lining of the ovary to its interior, where maturation to a viable egg cell can take place. The procedure, dubbed OvaPrime, will not be available in the US, however.

OvaScience’s initial offering, Augment—a process intended to improve the energy status of eggs used in IVF procedures by supplementing them with mitochondria derived from oogonial stem cells—has already run into a regulatory barrier. In 2013, the US Food and Drug Administration (FDA) informed the company it needed to file an investigational new drug application for the procedure, whereas OvaScience claims Augment is eligible for use as a 361 HCT/P, meaning it is covered by the FDA’s Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P’s) Product List and Section 361 of the Public Health Service Act.  Randomized clinical trials are not the norm in the fertility sector. “People are attempting to apply a high level of scientific rigor to an area that is not accustomed to it,” says Andrew Fein, analyst at HC Wainwright & Co. in New York.  

In the meantime, Augment is available in four territories only, Canada, Dubai, the UK and Turkey. As Nature Biotechnology went to press, the first baby conceived through the Augment process was due to be born. “The way the company foresees this playing out is after a few years of positive experience ex-US—US-based women will ask or essentially lobby the FDA for access to this technology,” Fein says. The example of egg freezing offers a precedent. “Demand in the US dictated its availability in the US,” he says.

David Sinclair, another scientific founder of OvaScience, alluded to the potential of CRISPR-Cas9 in germline engineering at an investor presentation, Fein says, but it is not part of the company’s research agenda at present. “They have enough headaches at this point without adding fuel to the fire.”

The US Department of Agriculture (USDA) on February 13 approved the first genetically modified (GM) apple developed to resist browning.  The Arctic apple’s go-ahead is a notable achievement for Canadian firm Okanagan Specialty Fruits, as the small biotech is one of the few to have successfully moved a GM plant through the regulatory process on its own. Indeed, two weeks after the apple’s launch, Okanagan announced its acquisition by Germantown, Maryland-based Intrexon, a synthetic biology company. Okanagan’s stockholders will receive $10 million in upfront cash and $31 million in Intrexon common stock. Industry observers now question whether the Arctic apple will carve a niche in the fruit tree industry or get caught up in the GM labeling debate.

Pre-cut fruit and vegetables are a growing trend in the food industry. “The [nonbrowning] trait will enable food service companies to cut and package the apples without adding browning inhibitors such as calcium ascorbate”—an antioxidant that changes the flavor of the apple, says Neal Carter, founder of the Summerland, British Columbia–based Okanagan. About 22,000 trees will be planted in the US this spring, with the resulting fruit available in fall 2016 for product demonstration, he says. Okanagan has also applied for regulatory approval of its apple in Canada.

Browning is caused by polyphenol oxidases (PPOs) naturally present in fruit and vegetables. When fruit is cut or bruised, these enzymes catalyze the oxidation of polyphenols to quinones, causing oxidative browning. The damage is superficial but can affect the taste and texture of the apple as well as its cosmetic qualities. In the Arctic varieties, the GM apples were genetically engineered with a transgene that produces specific RNAs to silence the expression of at least four browning PPO genes. The apple RNA sequences were introduced into Granny Smith and Golden Delicious varieties, where they bound complementary RNA to form a double strand. As RNA is single stranded, the double-stranded sequence is read as a mistake, and the plant’s naturally occurring Dicer enzymes are sent to chop it up, resulting in no or significantly fewer PPO proteins being produced.

RNA interference (RNAi) was also used by JR Simplot of Boise, Idaho to silence PPO production in nonbrowning potatoes, which were approved by the USDA in November (Nat. Biotechnol. 33, 12–13, 2015). For that product, fragments of a single potato PPO gene were re-introduced into potato, activating the RNAi pathway. But unlike the apple, the potato’s double-stranded RNA is formed by an inverted repeat transcribed in the tuber and processed into small interfering RNAs that ultimately silence their targets. JR Simplot’s crop was also modified to have reduced acrylamide, which was achieved by using RNAi to silence the asparagine synthetase-1 gene (ASn1).

Apples that won’t brown could make them more appealing to consumers and could also reduce waste by minimizing discarded apple due to bruising. But at least three growers associations urged US and Canadian regulatory agencies to reject Okanagan’s petitions for approval. Their objections were not made because of human health or safety concerns. In separate letters, the US Apple Association, the Northwest Horticultural Council and the BC Fruit Growers Association said GM apples may cause severe market disruptions, particularly in apple export markets averse to genetically modified organisms (GMOs). US Apple, however, changed its tune once USDA approval became imminent. “We are confident from the assurance we’ve received from Okanagan that they intend to stand by their pledge to clearly identify their apples in all marketing and packaging,” enabling consumers to choose between GM and non-GM apples, says Wendy Brannen, director of consumer health and public relations at US Apple.

Okanagan’s apples will not be labeled ‘GM’, but packaging will include the ‘Arctic’ name and logo. “It will be highly recognized as a GM product, given the amount of media attention we’ve had,” says Carter at Okanagan. The company has not yet decided whether the packaging will use other descriptive words, such as ‘nonbrowning’, which will partly depend on guidance from the US Food and Drug Administration, Carter says.

The GM apple may get caught up in the GMO labeling debate and used as an example, given its cachet as a family friendly, wholesome food, says Chris Schlect, president of the Northwest Horticultural Council in Yakima, Washington. “Apples are a symbolic product. It’s a fruit that a mother gives to a child going to school,” he says. “It’s going to be used in the media and by Congress in issues over the national labeling initiative.” Indeed, the Washington, DC–based Environmental Working Group put out a press release in February saying the approval of Arctic apples “underscores the need for a transparent and consistent national labeling standard.”

Other consumer groups argued against the safety of Okanagan’s apple. The Center for Food Safety (CFS) said USDA’s environmental assessment was inadequate—a complaint the Center has made for nearly every biotech crop assessment USDA has conducted in recent years. In its 61-page comment, the Center said that proper characterization of the PPO genes, their functions and the impacts of silencing them in the apple tree as a whole was not conducted. “I was floored by that,” says Martha Crouch, former professor of biology at Indiana University in Bloomington and a consultant for CFS. “It seems like that would be the minimum you would want to know before you start an assessment.” The Center noted that PPO genes have been shown in other plants to be associated with pathogen resistance, and that silencing them could lead to more susceptibility to disease and pests.

Okanagan says it conducted pest- and disease-resistance studies, and supplied the data to the USDA upon the agency’s request. “We have not seen any difference in disease susceptibility or plant pest risk between Arctic and control apple fruit or trees,” says Carter. “As summarized and analyzed in our petition document, we monitored all common orchard pests and diseases, including storage rot, over multiple years and multiple sites and saw no difference.”

Emily Waltz, Nashville, Tennessee 

Amgen’s Neupogen, the first biosimilar for which has been given the FDA’s blessing. @Bayne Stanley/Alamy

Sandoz’s biosimilar drug is about to become the first drug approved under the FDA’s biosimilar pathway. On January 7, the US Food and Drug Administration’s (FDA’s) oncologic drugs advisory committee voted unanimously to recommend approval of Basel-based Sandoz’s granulocyte colony stimulating factor filgrastim, a biosimilar of Thousand Oaks, California–based Amgen’s $1.2-billion seller Neupogen. Six years after Sandoz’s biosimilar filgrastim was approved in Europe, with 7.5 million patient-exposure days to support approval, it would seem a reasonable bet that the drug, whose proposed brand name is Zarxio, will get a green light on March 8, as Nature Biotechnology goes to press.

If so, it would mark a very long-awaited victory for biosimilars developers. The FDA’s biosimilar pathway was created in 2012 under the Biologics Price Competition and Innovation Act (BPCIA) after years of wrangling with originator firms. Zarxio’s launch would be symbolic of FDA’s broader blessing—at least in principle—for a whole new generation of cost-effective products. Zarxio, if approved to treat chemotherapy-induced neutropenia and related conditions, could save $5.7 billion in drug costs over the next decade, estimates US pharmacy benefit manager Express Scripts. No wonder New York–based Pfizer on February 5 deepened its commitment to biosimilars (and other hard-to-make generics) by a $17-billion bid for Lake Forest, Illinois–based Hospira, which is involved with two of the four known biosimilar submissions to FDA.

But if approval appears likely for Zarxio, several other barriers to commercial success remain (Nat. Biotechnol. 31, 264, 2013). Indeed, given the already relatively onerous nature of the US biosimilar pathway—known as 351(k)—“if this product doesn’t successfully launch, the biosimilar pathway is killed,” according to one Washington, DC–based expert who wants to remain anonymous.

What can go wrong? If Amgen gets its way, the courts could block, or at least delay, Sandoz (a division of Novartis) from launching. Amgen has thrown various accusations at the Swiss firm, ranging from not following the BPCIA rules over sharing information about its submission, to outright patent infringement.

Litigation aside, there remain unanswered questions around the product’s generic name and its label, just weeks away from the March 8 PDUFA (Prescription Drug User Fee Act) date. It’s unclear whether Zarxio will enjoy the same international nonproprietary (INN) name as the originator drug. FDA has yet to issue its promised guidance on biosimilar naming and faces strong pressure from innovator companies to mandate distinct INNs for each biosimilar product, purportedly to facilitate adverse event tracking. But ODAC member James Liebmann declared that the group had reviewed the drug as “filgrastim,” and that calling it anything else would be misleading. Sandoz agrees, pointing to the many US-marketed biologics that currently share an INN without any safety or traceability issues. “We’re sticking to our position that a brand name is the most useful” and that creating a new naming system is completely unwarranted, says a Sandoz spokesman.

FDA is unlikely to insist upon a completely different INN for Zarxio, but could suggest a hyphenated name, speculates Ronny Gal, a senior analyst at Sanford C. Bernstein in New York. A prefix wouldn’t be a disaster—Petah Tikva, Israel–based Teva’s long-acting Granix (filgrastim), approved as a novel biologic and launched in late 2013 as TBO-filgrastim, has about 15% market share by volume. But it would put another brake on the likely uphill battle convincing clinicians that the drug is clinically the same as Neupogen. It could also create headaches for pharmacy IT systems, including, for example, on alphabetical medication lists where the product would not appear with other filgrastims.

Sandoz doesn’t yet know how similar Zarxio’s label will be to the originator drug’s either. Biosimilar firms can apply for their products to be labeled ‘interchangeable’ with the originator drug—a designation that ostensibly supports automatic substitution by pharmacists, though several states have passed laws banning such action anyway (Nat. Biotechnol. 31, 269–270, 2013). For now, on FDA’s advice, Sandoz hasn’t applied for interchangeability; filgrastim is mainly a hospital-administered drug, anyway. But FDA may do so in future. “The standard for that [interchangeability] will include several years of real world use of the biosimilar, at least for the first ones,” opines Michael McCaughan, co-founder at Washington, DC–based information services firm Prevision Policy. But whether Zarxio is in the meantime labeled “noninterchangeable,” playing into the hands of those seeking to block widespread biosimilar uptake, remains to be seen. “Drugs aren’t normally labeled for what they’re not,” says Gillian Woollett, senior vice president FDA Regulatory Strategy and Policy at Avalere Health in Washington, DC. But there’s little that’s normal or straightforward so far about the road to biosimilar approval in the US.