Research Roundup: US and European efforts to address growing antimicrobial resistance and legislation to advance medical breakthroughs

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.

This Monday, May 18 was HIV Vaccine Awareness Day (HVAD), and GHTC members AVAC, the International AIDS Vaccine Initiative (IAVI), and the Bill & Melinda Gates Foundation convened leaders in the field to discuss the state of HIV and AIDS vaccine research and development (R&D). The discussion—which was hosted as both a briefing for congressional staffers and a dialogue among partners—included Dr. Gaudensia Mutua of the Kenya AIDS Vaccine Initiative, Dr. Yegor Voronin of the Global HIV Vaccine Enterprise, and Michelle Dees of IAVI. With worldwide investment in HIV and AIDS vaccine research on the decline since 2007 and some members of Congress calling for further cuts to US investment in this area, the discussion illustrated four key reasons why now is the time to ramp up—rather than scale down—investment in HIV and AIDS vaccine R&D. (1) We are closer than ever to developing an HIV and AIDS vaccine Despite the complexity and mutability of the HIV virus and the difficulty of producing a vaccine, there are currently thirty different HIV and AIDS vaccine candidates in the research pipeline. To ensure that the best candidates advance, strong investments are needed to support this diverse portfolio of vaccines. While most of these candidates are still being tested for safety and for evidence of an immune response, one candidate has already demonstrated partial efficacy. The evidence from that clinical trial has since been used to adjust the vaccine regimen, and the new regimen is currently being tested in another round of clinical trials. (2) We cannot eradicate HIV and AIDS without a vaccine While we have made immense progress in combatting HIV and AIDS with AIDS-related deaths falling by 35 percent since the peak in 2005, eradication will not be possible without a vaccine. For every one person who starts treatment, two more are infected, resulting in 2.1 million new infections and 1.5 million AIDS-related deaths each year. The stigma surrounding the disease continues to impede diagnosis and treatment efforts globally. While existing tools—from antiretroviral treatment to voluntary male circumcision—have had a major impact on reducing the spread of the disease, a vaccine is needed to completely protect against infection. (3) Investments in HIV and AIDS vaccine R&D are producing broader impacts on global health The HIV virus is highly mutable, and is constantly adapting to better fight the immune system. Consequently, many of the standard approaches to vaccine R&D have not proved fruitful. One of the most common types of vaccines—a live attenuated vaccine—involves the use of a weakened, but live version of the pathogen to stimulate the immune system to develop antibodies. The mutability of the virus has made this approach impossible and unsafe. Alternately, scientists often examine the immune response of a survivor to develop a vaccine that will imitate or enhance that process. As no one has ever rid their body of the HIV virus once infected, researchers started the search without a roadmap for what might work. While developing a vaccine that can defend against an ever-changing virus has been a major challenge for scientists, the search has led to invaluable insights into the immune system and progress in vaccinology writ large. Additionally, investments in strengthening HIV and AIDS vaccine R&D capacity in endemic countries have produced broader research and health benefits. For example, the Kenya AIDS Vaccine Institute (KAVI) in Nairobi, Kenya, was established primarily to gather data and conduct clinical trials. However, in addition to the 11 vaccine candidates it has tested in the past 14 years, the institute trained more than 1,500 people between 2010 and 2014. These trainees have been educated in everything from laboratory management and clinical practice to grant writing and vaccine literacy. Additionally, the KAVI facility has been used to test vaccines and drugs for other infectious diseases including Ebola, has helped provide trial participants access to treatment options they may otherwise not have received, and has played a role in combating the stigma of HIV and AIDS in the local community. (4) A vaccine for HIV and AIDS would have enormous financial benefits While the human impact of HIV and AIDS is more than enough reason to invest in vaccine R&D, the continued financial cost of treatment should also be noted. The President’s Emergency Plan for AIDS Relief, which reaches nearly 5 million people each year, spends US$338 per patient per year on HIV and AIDS treatment, and that’s down from an initial $1,100. A vaccine could prevent between 5.2 and 10.7 million new infections and could consequently save $46 to $95 billion over ten years—just in treatment costs. For more information, check out these key messages from AVAC or this video featuring researchers and clinicians across the HIV vaccine field.