Jill Wechsler is Pharm Exec's Washington Corespondent

Jill Wechsler

	Can a commitment to limit prices to ensure patient access to important new medicines regain public trust and confidence in the biopharmaceutical industry? That’s the hope of a large cadre of biotech company executives who recognize that recent scientific advances that promise to cure critical diseases must be linked to high integrity and corporate responsibility or face price controls and other policies that undermine support for continued discovery of new medicines. 

	In a “New Biotechnology & Pharmaceutical Industry Commitment to Patients and the Public” penned by six CEOs, more than 200 leaders from some 150 small and mid-size firms and research organizations 

acknowledge that out-of-pocket costs for individuals must be limited to sustain support for fiscal and patent policies key to advancing innovation

. The group led by executives from Amicus, Nkarta, Ovid, Global Blood, GlycoMimetics and Alnylam Pharmaceuticals back collaboration with healthcare entities, including payers, hospitals, and distributors, in efforts to eliminate co-pays and deductibles for all patients. 

	Those signing the commitment letter also pledged to support ethical business practices and to invest “only in novel therapies that address unmet patient needs.” And they oppose companies and stakeholders who “abuse this commitment to patients and who abuse policies aimed at fairly rewarding innovation.” At the same time, the group supports the marketing of biosimilars and generic drugs after “legitimate patents and regulatory protections expire.” 

	By itself, the public letter offers few specifics for effective change in current industry practice. Even so, the list of supporters is notable for the absence of big pharma and biotech firms who did not sign on, ostensibly due to legal concerns about joining any industry initiative that could be construed as involving multi-company price-setting agreements. The Biotechnology Innovation Organization (BIO) voiced support for the principles expressed here by many of its members, but did not officially endorse the statement. And while manufacturers can face stiff penalties for actions even hinting at price-setting agreements, these commitments to ethical practices should avoid such consequences by emphasizing responsible actions by individual companies. 

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More than 200 biopharma leaders acknowledge that out-of-pocket costs for individuals must be limited to sustain support for fiscal and patent policies key to advancing innovation.

Biotech Execs Pledge “Reasonable” Price Increases

	FDA did not set any records last year in approving new drugs and biologics for market, but it did speed a number of important new therapies to patients, in continuing to demonstrate its flexibility and support for biomedical innovation. Based on its criteria, the Center for Drug Evaluation and Research (CDER) approved some 50 new molecular entities (NMEs) in 2019, a count that may vary 

. In addition, the Center for Biologics Evaluation and Research (CBER) approved the first gene therapy for spinal muscular atrophy, Novartis’ Zolgensma, as well as new vaccines for Ebola (from Merck) and Dengue (Sanofi). While the totals fall short of the record-setting 59 NMEs approved in 2018, the numbers are close to or exceed the agency’s performance in most previous years. 

	Probably more important than the number is the wide range of break through therapies moving through the agency’s review process, including nearly a dozen cancer treatments, some with innovative modalities. Speedy approvals at the end of the year included the first PARP inhibitor to treat advanced pancreatic cancer, Lynparza, from AstraZeneca and Merck. FDA also approved two antibody-drug conjugates (ADCs), one for urothelial cancer from Seattle Genetics and Astellas Pharma, and another for advanced breast cancer from Daiichi Sankyo and AstraZeneca. 

	Earlier, Vertex Pharmaceuticals gained a fast approval for a new triple-combo treatment for cystic fibrosis, Trikafta, while new therapies for complicated urinary tract infections came from Shionogi and Merck. Particularly noteworthy is the success of two new drugs for sickle cell disease, which largely affects African Americans. These include Novartis’ Adakveo and Oxbryta from Global Blood Therapeutics. The list also includes important new drugs for postpartum depression from Sage Therapeutics, Intra-Cellular’s Caplyta for schizophrenia in adults, new migraine therapies from Eli Lilly and from Allergan, plus a new Novartis drug for a relapsing form of multiple sclerosis. 

	Most surprising was FDA’s decision in December to approve Sarepta Therapeutics’ second drug for Duchenne muscular dystrophy, Vyondys 53. The agency had rejected the application only four months earlier. 

	Speedy review from FDA, as well as high launch prices for many critical new drugs, will continue to raise controversy. Some critics claim the agency is moving too quickly in bringing new therapies to market based on limited testing, while others argue that FDA remains too slow in addressing the critical needs of many patients. And high price-tags, particularly for some treatments for larger patient populations such as sickle cell disease, are sure to accelerate calls for pharmaceutical price controls. So far, Congress has stepped back from legislation to limit outlays for prescription drugs, but the debate will be aggravated by a number of new medicines with six-figure annual costs, as well as a large number of annual January increases in list praises for hundreds of brand medicines.  

While not setting any records for the rapid approval of new drugs in 2019, FDA did speed a number of important new therapies to patients, writes Jill Wechsler.

New Drug Approvals Stay Strong in 2019

	FDA has an official new leader, following a Senate vote to confirm Stephen Hahn as the agency’s next commissioner. Hahn comes to FDA from the MD Anderson Cancer Center in Houston, where he was chief medical officer. Despite his lack of experience in the federal government, he benefited from broad support from dozens of patient groups and research entities, as well as a strong list of five former FDA commissioners. Regulated entities and most stakeholders affected by FDA programs usually prefer that the agency have a clear leader, as opposed to less authoritative temporary directors. 

	Hahn lost some support in the Senate from Democrats due to a limited commitment to taking action to against teen vaping of flavored e-cigarettes, a controversial area that has suffered from unclear administration policy. At the same time, Hahn demonstrated his political skill by indicating strong interest in numerous hot policy issues during his Senate confirmation hearings, without making clear commitments to specific actions. 

	Although Hahn’s role at FDA may be short-lived if there is a change in administration next November, he faces a broad range of hot-button issues that require more immediate attention. FDA is under pressure to do more to address the deadly opioid epidemic, to weigh importation of less expensive drugs from other countries, to clarify polices for marketing cannabidiol products, and for supporting the development of new breakthrough therapies filling the new drug pipeline. A main task for the commissioner is to make the case to Congress and the administration for strong funding for FDA, despite partisan hostility on Capitol Hill and administration efforts to cut federal spending. And the high cost of new cutting-edge therapies will remain a high-profile issue, raising questions about FDA vetting of the long-term benefits and risks of new treatments.

FDA has an official new leader, following a Senate vote to confirm Stephen Hahn as the agency’s next commissioner. 

Hahn Confirmed as FDA Commissioner

	The development of new therapies to treat orphan diseases is particularly perilous, due to limited patient populations, high costs, and difficulty in measuring clinical effectiveness. FDA officials are addressing these issues through the Rare Disease Cures Accelerator (RDCA) initiative in the Center for Drug Evaluation and Research (CDER). The goal is to shift away from a system of fragmentary research methods plagued by poor quality evidence to a more coordinated research approach and methods that can expedite development of drugs to treat some of the 7,000 rare diseases affecting 25,000-30,000 people. 

	Main strategies involve establishing common platforms and standardized tools and infrastructure to improve the quality of clinical trial data, explained Theresa Mullin, CDER acting director for strategic initiatives, at the “rare summit” sponsored by the National Organization for Rare Disorders (NORD) in Washington, D.C. last week. Mullin described how a more cooperative and collaborative approach can improve the quality of study endpoints, promote trial designs that accelerate learning, reduce mis-steps that cause failures and delays, and generate evidence needed for regulatory approval.

	The RDCA provides the infrastructure for a cooperative approach to designing and conducting clinical trials in rare diseases to improve testing, protocols, and patient enrollment in clinical trials, Mullin noted. FDA is collaborating with the Critical Path Institute, NORD, patient groups, industry and other stakeholders on a framework for conducting more standardized rare disease natural history studies to help target treatment and design appropriate clinical trials. This involves examining the underlying causes of a disease, how it changes over time, variables in symptoms and experiences, and how the disease differs across patient populations. Patient perspectives remain key to providing insight into the most important impacts and what constitutes “meaningful change” in symptoms. 

	Similarly, the RDCA Data Analytics Platform (DAP) aims to house integrated patient-level data from diverse sources, including clinical trials, observational studies, patient registries and real-world data from electronic health records, noted FDA acting commissioner Ned Sharpless at the NORD conference. A goal of the initiative, he pointed out, is to facilitate sharing of existing patient-level data to inform disease characterization and clinical trial design to accelerate development of new rare disease therapies. 

	Another key RDCA component involves devising core sets of clinical outcomes assessments (COAs) to measure treatment impacts that matter most to patients and ideally are applicable to more than one rare disease. A new CDER grant program supports the development of core COAs and related endpoints, including those impacts that matter most to patients and are likely to demonstrate change. 

	A more long-term RDCA goal is to establish a global clinical trials network able to facilitate the launch and conduct of studies involving rare diseases, Mullins added. Investigators and sites in the network would provide more uniformity and expertise in planning and conducting studies for rare disease therapies and ensure the collection of high quality data.

	The RDCA initiative is supported by some of the $10 million in last year’s FDA budget provided by Congress to support innovation in advancing treatments for rare diseases. FDA’s Office of Orphan Products Development (OOPD) recently awarded two grants for natural history studies at academic research centers, one measuring acute pain in infants and young children, and the other assessing physical function across a range of chronic conditions. And 12 new grants to fund clinical trials involving rare disease therapies, building on FDA’s long-standing program to support researchers conducting clinical trials in this area, particularly to advance treatments for pediatric rare diseases. 

	On a broader level, RDCA initiatives aim to advance common approaches and more sharing of research goals and methods to build on commonalties for developing new orphan drug therapies, Sharpless observed. He noted that FDA will continue to provide expedited review pathways for promising rare disease treatments and will issue more guidance documents to spur development of new pediatric medicines and gene therapies for rare diseases. And researchers receiving orphan products grants from FDA will contribute to discussions of common considerations for successful completion of rare disease studies. 

CDER's Rare Disease Cures Accelerator initiative looks to foster a coordinated research approach and methods that can expedite development of drugs to treat some of the 7,000 rare diseases. 


New FDA Model Aims to Speed More Rare Disease Treatments to Patients

	Under a new “knowledge management” approach for the Center for Drug Evaluation and Research (CDER), sponsors will submit applications that present data in a structured format so that it can be transmitted to teams of experts from multiple disciplines able to assess applications for new drugs and biologics in a timely and efficient manner. The aim is to shift sponsors away from long, narrative documents filed in PDF format that are repetitive and obscure important issues. Instead, CDER assessment teams composed of medical reviewers, pharmacologists, statisticians, pharmacists and other specialists as needed will examine the data to answer specific questions relevant to the product under review.

	CDER director Janet Woodcock is finalizing this process for assessing and approving new drugs in order to be able to handle a surge in submissions that reflects important advances in biopharmaceutical science, as well as the digital revolution that has expanded exponentially the data and information supporting biomedical research. Our understanding of clinical pharmacology, and the vast amount of data from gene sequencing, she commented, along with greater scrutiny of the value of new medical products, require “a new approach” for providing an assessment – not a review – of new drug applications (NDAs) and biologics license applications (BLAs).

	FDA hopes that this process, moreover, will make new treatments more affordable. The aim is to find out early if patients will be better off or not from access to a new treatment, Woodcock observed at the recent Biostatistics Industry & Regulator Forum sponsored by the Drug Information Association (DIA) and FDA, acknowledging that greater scrutiny of drug value is currently a major topic of debate.

	To be able to assess more applications for increasingly complex medicines, review teams will identify key issues during the IND stage to be able to focus on them efficiently and with appropriate expertise. An assessment document will present a benefit/risk evaluation, the drug development program, key issues and recommendations, aiming to provide a more transparent process and clarity for advisory committees. The aim is to finish this initial assessment midway through the review period to leave ample time for FDA and the sponsor to discuss post-market research commitments and the need for a REMS (Risk Evaluation and Mitigation Strategy) well before approval deadlines. This will lead to “high quality, more uniform work products,” Woodcock said, “with fewer surprises and last-minute changes.”

	The new assessment process also involves a significant reorganization of CDER’s Office of New Drugs (OND). It will expand from six to eight offices to better provide patients and researchers with clearly identifiable experts in leading disease areas: neuroscience (including pain and addiction); inflammation/immunology (rheumatic, transplant therapies); internal medicine (diabetes, hematology); oncology; human reproduction (urology, OB-GYN, pediatrics, maternal health); over-the-counter (OTC) drugs; and other treatments (ophthalmology, medical imaging, compounding).

	OND also will have a centralized project management group to ensure that all divisions and teams follow consistent processes and to help external stakeholders and other FDA operations identify appropriate contacts. And a new OND policy office will support the development of guidances and other documents.

	These changes will form the basis for a more automated CDER work flow management system based on standard processes and protocol assessment templates that will result in more timely regulatory decisions. The aim is to move away from multiple, and often repetitive, individual staff reviews. OND is trying out this team approach on a few applications and hopes to have it in place by the end of this year.

	Looking to the long-term, Woodcock envisions the data-based assessment process will provide a model to reform how CDER manages post-market safety issues. Eventually data submitted by sponsors may move to the “cloud” in standardized formats to facilitate data exchange and analysis.  These innovations reflect a “big cultural change” that will take some time to accomplish, Woodcock acknowledged. But with the rise of patient-focused drug development, genetic targeting to treat rare conditions, demand for greater transparency in the regulatory process, and more startup biotech companies focused on innovation, she believes that FDA needs  new approaches for dealing with these and future challenges. 

A new CDER “knowledge management” approach will see companies submit applications that can be transmitted to experts from multiple disciplines able to assess applications for new drugs and biologics in a timely and efficient manner. 

FDA Moves to Modernize Drug Review Process

	To better manage a growing number of applications for new drugs that treat disease in innovative ways and involve new kinds of clinical research programs, FDA officials are mapping plans to restructure the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER). A main goal is to “flatten the organization,” explained CDER director Janet Woodcock, with more reviewers authorized to make decisions on

 review findings. This shift to smaller review divisions should reduce bottlenecks in the review process, she explained at the annual meeting of the Food and Drug Law Institute (FDLI) last week in Washington, D.C. An OND reorganization steering committee heads up the effort, and, she emphasized, the review program modernization effort is “proceeding according to plan.”

	Commissioner Scott Gottlieb similarly highlighted how OND modernization will help FDA adapt to important scientific changes in medicine. The overall aim, he explained in a keynote speech at the FDLI meeting, is to better align new drug development and review with new types of medicines designed to target molecular changes that initiate disease, and “not just the symptoms of illness.” This shift will require new approaches to documenting and evaluating applications, including a team-based review process that brings together staff with expertise in areas such as statistics, modeling, simulation, and advanced manufacturing to assess novel trial designs and drug development approaches.

	“We want it to be easier to innovate the way drugs are developed,” Gottlieb commented. Our professional staff members are “thought leaders in their disciplines,” he observed, “and we want to give them more time to collaborate with academic medical scientists and patients, to analyze scientific and commercial developments, and to strategically foster drug development.”

	The process for documenting reviews will be revised to highlight issues and data of greatest importance, while also reducing the sometimes-redundant memos generated by multiple review processes. Woodcock noted that CDER staffers are developing a new template for documenting multiple aspects of a review, including toxicology, clinical pharmacology, and clinical review.

	A new Office of Policy in OND will play a key role in developing more consistent policies and procedures across disease areas, Woodcock added. This office will facilitate the development of more “bullet guidances” that provide short, timely advice on specific topics involved in developing certain therapies. Such guidances are faster to draft and to finalize, and CDER hopes to issue 30-40 such advisories a year.

	Gottlieb further described the OND changes at the annual meeting of the Reagan-Udall Foundation the next day, noting that he expects CDER to begin unveiling these initiatives by the end of this summer. The OND reorganization will establish more focused therapeutic divisions, he explained, such as separating the current Division of Gastroenterology and Inborn Errors Products into divisions for gastroenterology and for liver disease. He also anticipated that a common review template would reduce the multiple memos developed by each review discipline.

	Such a broad and complex reorganization of this important CDER operation, involving the formation of new review divisions and a new policy office, will take time to move through the formal federal government review process, Woodcock pointed out. Yet, she and her staff have orchestrated such restructuring efforts for generic drugs and for drug quality oversight in recent years, and she anticipates a similarly successful modernization effort for the new drug review process.

FDA officials make efforts to better manage the increasing amount of applications for new drugs that treat disease in innovative ways and include new kinds of clinical research, starting with a plan to restructure the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER).