Breakthroughs Blog: FDA

21st Century Cures.Last week, the House Energy and Commerce Committee unanimously voted to approve the 21st Century Cures Act—a bill that aims to speed the development, approval, and introduction of new health technologies.Clocking in at over 300-pages, the legislation is packed full of proposed changes to the way health products are developed by the US National Institutes of Health (NIH) and regulated by the US Food and Drug Administration (FDA). Below, GHTC breaks down a few of the proposed changes that could matter most to global health researchers, product developers, and advocates.NIH receives boost in funding The legislation would reauthorize the NIH for the next three fiscal years (FY) and boost funding over that period, starting with US$31.8 billion in FY 2015 and increasing to $33.3 billion and $34.8 billion in FY 2017 and 2018 respectively. (As a reference, current NIH funding is around $30.3 billion.) It is important to note this boost is in discretionary spending, rather than mandatory spending, so these increases could still be subject to spending caps and sequestration cuts which in the past have significantly reduced NIH’s budget.The legislation would also provide $10 billion in new NIH funding over the next five years through the establishment of a new “NIH Innovation Fund.” This pot of money is mandatory spending, and thus would NOT be subject to spending caps and sequestration. The legislation mandates that at least $500 million per year of the fund would go to a new Accelerating Advancement Program, which seeks to address unmet medical needs in the United States including infectious diseases and neglected tropical diseases and antibiotics.The legislation would also mandate that the NIH, and the centers and institutes within it, develop five-year strategic plans to guide research activities. The language defining how NIH must use portions of the funding is unlike current NIH funding allocations and has some concerned that Congress is being too prescriptive with scientific research.NCATS permitted to expand into later stage research Photo: National Institute of Allergy and Infectious DiseasesThe Cures Act would remove current restrictions that prohibit the National Center for Advancing Translational Sciences (NCATS) at NIH from supporting clinical trials beyond phase IIA—the first round of trials to test efficacy, rather than just safety of a treatment in humans.NCATS was created to help advance translational science, particularly for rare diseases in the United States. At the time it was created, Congress prohibited the center from conducting later stage clinical research out of fear that it would then be competing with and duplicating private-sector product development activities. This legislation lifts that prohibition, extending NCATS ability to conduct trials through stage III—the final pre-market stage where safety and efficacy of a treatment are tested in in large groups of individuals.Many global health conditions qualify as rare diseases under the program’s definition because they impact fewer than 200,000 people in the United States, meaning this legislation change could permit NCATS to support later stage clinical research for many neglected diseases and other global health conditions.Bill promotes pediatric research Under the legislation, NIH would be required to establish a national pediatric research network to pool resources and coordinate activities on pediatric diseases. This legislation also encourages the NIH and FDA to work with the European Union, industry, and other partners to establish a global pediatric clinical trials network.Drugs often react differently in children than they do in adults, and creating pediatric-specific treatments has proved challenging for researchers and product developers producing treatments to be used both domestically and globally. This legislation seeks to overcome some of these challenges by promoting development and testing of pediatric formulations of drugs.Congress acknowledges importance of agency participation in scientific conferences The act includes a sense of Congress acknowledging the importance of participation in scientific conferences and meetings for both NIH and FDA employees. While the legislation doesn’t go so far as to lift existing restrictions or provide funding for participation, Congress’s recognition of this importance is a critical step forward.A GHTC analysis found that many agency representatives cite a lack of funding for participation in scientific conferences as a serious hindrance to enhancing coordination and collaboration among agencies engaged in global health research and development (R&D).Increases use of biomarkers and surrogate endpoints as clinical evidence at FDA Photo: FDA/Michael J. ErmarthThe legislation paves the way for the FDA to rely on biomarkers and other surrogate endpoints to accelerate product approval for a broader category of products. Proving that a product or treatment can successfully produce the desired clinical endpoint—may not be feasible in certain circumstances or can often require clinical trials that are large, long, and costly. So in some cases, trial sponsors have proposed using biomarkers—or biological indicators—that are correlated with the clinical endpoint as a substitute to assess the efficacy of a treatment or product more easily. For example, to measure whether a treatment prolongs cancer survival—a clinical endpoint—one might assess a surrogate endpoint like whether the treatment succeeds in shrinking tumors.At the moment, the FDA permits use of surrogate endpoints for accelerated approval for drugs intended to treat a narrow category of patients with life-threatening illnesses and unmet needs. The bill calls on the FDA to establish guidance for use of qualifying biomarkers and work with sponsors to establish parameters that would allow for approval of a broader set of products using surrogate endpoints.Use of surrogate endpoints poses both benefits and challenges. It could lower R&D costs and reduce the length of time needed to conduct clinical trials, thereby accelerating the availability of treatments. However, at the same time, it can often prove difficult to determine if a surrogate endpoint or biomarker is a reliable indicator that the product has the intended clinical benefit. For example, elevated cholesterol levels are linked with heart disease, but at the same time, it is possible that a drug that reduces cholesterol will have no measurable impact in preventing deaths from heart disease.Spurring antibiotic drug development If enacted, the Cures Act would create a new expedited FDA review pathway for antibiotics intended to treat “a serious or life-threatening disease, condition, or indication” and intended for use in a limited target population. This new pathway could allow the FDA to approve a product based on earlier Phase II trials and surrogate endpoints, rather than larger, later-stage Phase III clinical trials.Some organizations support this new pathway, arguing that it would expedite patient access to new antibiotics and help tackle growing antibiotic drug resistance. Others argue that this new pathway would allow products to be approved based on lower FDA standards, which could in turn put patient health and safety at risk.The bill would also increase Medicare payments to hospitals who use certain new antibiotics as a way to financially incentivize private-sector development of critically-needed new antibiotics. However, some critics of this provision argue that it would be counterproductive to the intended goals and would instead encourage overuse of new antibiotics, which would in turn hasten the development of drug resistant strains and further exacerbate the problem of antibiotic resistance.Changing the way medical devices are reviewed and approved Photo: FDAUnder the legislation, medical devices would be eligible for “breakthrough” designation by the FDA, which allow them to receive priority, expedited review.This new priority review program for devices is modeled after the breakthrough therapies program for drugs and is intended for “breakthrough technologies” for either conditions “for which no approved alternatives exist” or that would offer “significant advantage over existing approved or cleared alternatives.”In addition to creating this priority review pathway for medical devices, the legislation would also direct the FDA to take steps to ensure clinical trial designs for medical devices are “as efficient as practicable,” by exploring options such as the adoption of shorter or smaller trials, use of surrogate endpoints, or adaptive trial design.In an effort to further accelerate approvals of medical devices, the legislation would significantly alter the type of evidence the FDA could consider when reviewing a device for approval. This bill would allow the FDA to consider as valid scientific evidence case histories, registry data, studies published in peer-reviewed journals, and data collected in countries other than the United States. While this change could help speed the testing and approval of critically needed devices, critics argue it could also undermine FDA’s ability to ensure medical device safety and efficacy— citing the fact that case histories are anecdotal and lack a control group, while journal articles can often leave out critical information or can include mistakes, misrepresentation, or fraud, which the FDA may not become aware of if it relies solely on the published articles.Expansion of market exclusivity, but less than originally anticipated The legislation would extend by six months market exclusivity for drugs approved for a new indication or use for a rare disease or condition, extending a drug’s exclusivity period not only for the new indication, but for all of the drug’s indications.The purpose of market exclusivity is to help companies recoup the investments they made into R&D for a product or therapy and encourage future private-sector investment in research and product development. However, critics also note that extending market exclusivity delays entry of generics into the marketplace which can lead to increased costs for patients and limit affordable access to lifesaving health technologies. Product price can pose a significant barrier to access particularly in low- and middle-income countries.Earlier versions of the legislation featured additional provisions extending market exclusivity that were taken out of the version approved by the Committee. These included provisions which would have permitted the sale of market exclusivity to other companies and extended exclusivity for follow-on drugs and first-to-file American-made generic drugs.FDA receives increased funding To ensure FDA has the capacity to carry out its programming, the legislation would increase FDA funding by $550 million over the next five years. The bill would also exempt FDA user fee programs from sequestration spending cuts.While passage of the legislation through the Committee is a critical milestone, the act still has a long journey before it can become law. The legislation is expected to be voted on by the full House of Representatives in June. Meanwhile, parallel legislation is under development in the Senate. If both pass their respective chambers, the two versions will eventually have to be reconciled by both chambers before the legislation can be passed and then sent to the President for consideration. GHTC will continue to monitor this legislation as it develops.

United States Representatives Jim Cooper (D-TN) and Cynthia Loomis (R-WO) introduced the Research for All Act last week which calls for the inclusion of more women in clinical trials for products submitted for US Food and Drug Administration (FDA) approval. Drugs can have different effects on women and men, and as women are often underrepresented in clinical trials, there have been products on the market that are unsafe or less effective for women. While the FDA has made strides in recognizing and addressing this disparity and its potential consequences, this bill would require the FDA to “ensure that the design and size of clinical trials for products granted expedited approval … are sufficient to determine the safety and effectiveness of such products for men and women using subgroup analysis." Opponents fear that this legislation could increase the cost or length of clinical trials and consequently, product development. Mark Prausnitz, director of the Center for Drug Design, Development, and Delivery at the Georgia Institute of Technology, has created a small patch covered with 100 minute needles intended to administer vaccines without a syringe and needle. Not only would the vaccination be virtually painless, but it could be self-administered, and it would not need to be refrigerated, making it accessible in remote areas with a paucity of skilled health workers or unreliable electricity. The patch has been used successfully to administer the measles vaccine to animals, and clinical trials in humans are expected to start in 2017. Prausnitz will also be testing a flu vaccine patch on 100 volunteers this summer. While the vaccine’s cost will remain the same, Prausnitz hopes the patch will be cheaper than syringes and needles. Researchers at the University of Notre Dame have created simple, paper cards that can identify low-quality or counterfeit malaria medicines. The cards have 12 bars that change color when exposed to a crushed-up pill, and those bars indicate the presence and quantity of six different antimalarial agents. One third of antimalarials in sub-Saharan Africa are either entirely fake, diluted with different ingredients, or contain inadequate amounts of the antimalarial agents. These drugs can cause drug resistance and the additional ingredients can be harmful to patients. The cards, which currently cost US$0.50 each, are intended for use by pharmacists and customs offices, but only work for non-artemisinin-based antimalarials. The leading approach to treating river blindness—mass administration of the medicine ivermectin—can be deadly to patients co-infected with Loa loa worms. However, the detection of these worms can be a challenge, requiring a microscope and a health worker trained to identify the worms in the patient’s blood. Daniel Fletcher, a professor of bioengineering at the University of California, Berkeley, has developed a microscope that connects to a smartphone, takes a video of a blood sample, and detects the movement of Loa loa worms. The entire process takes about three minutes, a much shorter process than transporting a blood sample to a laboratory and counting the worms individually. While this device is an invaluable diagnostic tool, the article highlights the need for research and development of a drug that can combat both the Loa loa worms and the parasites responsible for river blindness.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. US Food and Drug Administration (FDA) Commissioner Dr. Margaret Hamburg announced last week that she intends to resign from her position in March. The FDA’s Chief Scientist Dr. Stephen Orstroff will serve as the interim Commissioner. Dr. Robert Califf, founding director of the Clinical Research Institute at Duke University, and recently appointed deputy commissioner for Medical Products and Tobacco at the FDA, is expected to be the principal candidate to fill the role permanently. The Global Health Innovative Technology (GHIT) Fund and the Gates Foundation launched a Grand Challenge last week to combat neglected diseases, including malaria, tuberculosis, Chagas disease, and visceral leishmaniasis. The Fund intends to grant US$2 million per year for the research and development (R&D) of new drugs, vaccines, or diagnostics, and up to $1 million per year for each product. GHIT also announced last week that it will invest $637,000 into the development and testing of chemical compounds in the pursuit of more effective products to prevent and treat malaria. The funding will be directed into a partnership between GHTC member Medicines for Malaria Venture and Japanese pharmaceutical company Daiichi Sankyo. Policy Cures—an independent research group and author of the annual G-FINDER report which analyzes global spending on global health R&D—released its first-ever report on reproductive health R&D for developing countries. The report reveals that just $88 million was spent on developing country-specific reproductive health R&D in 2013, $63 million of which was spent on contraceptive R&D. The report explores the limited funding and major gaps in reproductive health R&D, highlighting the need for affordable products that are easily delivered, administered, or stored; have multiple purposes; and do not have major side-effects. A recent study reveals that the United Kingdom’s top 25 universities—in terms of public funding for medical research—spend just 1.7 percent of their health research budgets on neglected diseases. The London School of Hygiene & Tropical Medicine topped the list, spending 68 percent of their health research on diseases that impact people in developing countries, however, all but 5 of the top 25 allocated less than 10 percent of their medical research budgets to neglected diseases.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. Last week the House Appropriations Committee easily approved the State and Foreign Operations Subcommittee’s (SFOPS) appropriations bill. Both chambers have also released their accompanying reports which provide policy language that gives further clarity on the policymakers’ thinking and intent. The US Food and Drug Administration (FDA) has released a guidance to assist sponsors in drug development for the treatment and prevention of neglected tropical diseases (NTDs) for low- and middle-income countries. The guidance is intended to represented the FDA’s current thinking regarding drug development for NTDs, including clinical trial designs and internal review standards to support approval of drugs. UK Prime Minister David Cameron has called for a global action plan to effectively treat drug-resistant superbugs. Prime Minister Cameron appointed ex-Goldman Sachs Chief Economist Jim O’Neill to lead the analysis on the issue and identify why few new antibiotics are being developed. The O’Neill Commission will also develop a plan for “encouraging and accelerating antibiotic development,” as well as explore incentive mechanisms for drug makers to produce antibiotics even if they are rarely used. Global Health Council (GHC) Executive Director Christine Sow recently wrote about the top ten trends shaping today’s global health outlook. Sow—who was made executive director of the GHC last November—went on a “listening tour” over the last three months to get a better sense of the global health community’s priorities and needs. The All-Party Parliamentary Group on global tuberculosis (TB) in the United Kingdom has released a new report on research and development for global health. The report seeks to explain why diseases that kill so many are neglected in research efforts, and provides a wide range of views and ideas on how to solve the problem.