Breakthroughs Blog: FDA

Dr. Robert Gallo co-discovered the HIV virus and subsequently led the development of the first HIV and AIDS blood test. Now, his team at the University of Maryland School of Medicine is initiating human clinical trials of an experimental HIV and AIDS vaccine that aims to prevent the virus from attaching to immune cells. The HIV virus uses a protein on its surface—gp120—to bind onto one part of human immune cells—the CD4 receptor—and then subsequently bind onto a second part of the cell—CCR5. This vaccine candidate interrupts this process by preventing the HIV virus from attaching to CCR5, therefore disrupting the process of infection. While many vaccines target specific viral strains, this candidate is intended to neutralize all strains of the HIV-1 virus. The first phase of the trial will enroll 60 healthy, adult volunteers to determine the vaccine’s safety and to ascertain if it successfully triggers an immune response. A 23-year-old engineer has developed an inflatable incubator that is designed to be easy to transport, use, and maintain, which could dramatically reduce deaths of premature babies in refugee camps. Developer Briton James Roberts has created electronic and functional prototypes which indicate that the incubator, known as MOM, will provide the required warm, stable, and sterile environment. Roberts designed the product with Syrian refugee camps in mind, as an estimated three-fourths of premature infant deaths in camps could be prevented with proper incubation. The incubator can be collapsed (see Figure 1) to fit in care packages commonly distributed in refugee camps and while it does require electricity, it can run off of a car battery or solar power. Roberts recently won two cash prizes to support product development and manufacturing but is continuing to fundraise to support the costly process of regulatory approval for medical devices. Roberts believes the product could be ready for market by 2018. Photo: CDC/ Dr. Scott Smith The US Department of Defense (DoD) and National Institutes of Health (NIH) have both supported the research and development (R&D) of drugs and vaccines for Ebola since the early 2000s. In both agencies, budget constraints halted progress despite promising clinical trials. In 2004, a researcher at army installation Fort Detrick was exposed to Ebola, prompting the DoD to partner with pharmaceutical company Sarepta Therapeutics to rapidly develop an experimental treatment for Ebola. The treatment was given emergency approval by the US Food and Drug Administration (FDA), but the researcher did not become infected and the treatment remained unused. In 2010, the DoD awarded Sarepta a US$291 million contract to continue its work. Sarepta’s drug demonstrated 60 to 80 percent efficacy in clinical trials with primates and proved safe for use in phase 1 human clinical trials. In September 2012, the FDA granted Sarepta’s drug fast-track status—to expedite its regulatory review—but just one month later, the DoD discontinued the project, in light of looming budget cuts that seemed inevitable due to congressional gridlock. In mid-2014, after the onset of the Ebola epidemic in West Africa, Sarepta CEO Chris Garabedian approached the DoD about the possibility of continuing their work, however, the agency chose to fund products that were not as far along as Sarepta’s. While the DoD has since reconsidered—inviting Sarepta to apply for funding for phase II trials—Sarepta declined, and under new leadership, has terminated their Ebola R&D. The US Department of Agriculture (USDA) has contracted two veterinary pharmaceutical companies—Harrisvaccines and Ceva Santé Animale—to manufacture, store, and ship vaccines to prevent the strain of avian influenza which caused an outbreak and consequent shortage of eggs and turkey in the United States earlier this year. The contract requires the companies to store the vaccines for up to five years, regularly testing them for quality assurance, and will ship them within ten days to anywhere in the United States if requested by the USDA National Veterinary Stockpile. To improve clarity and expediency of communication—for which the agency was criticized by veterinary, poultry, and egg groups during this year’s outbreak—the USDA has also worked with Iowa State University to translate avian influenza–related biosecurity materials for Spanish-speaking farm workers.

The zoonotic Middle East Respiratory Syndrome (MERS), which World Health Organization (WHO) Director-General Dr. Margaret Chan called “a threat to the entire world” has spread to South Korea. More than 100 cases and 10 deaths have been reported, making it the largest outbreak outside of the Arabian Peninsula. While there are currently no vaccines or treatments for MERS, researchers are confident that with adequate political will and funding, such products could be rapidly advanced. Photo: PATH/Nguyen Ba Quang Dr. Matthew Frieman, a professor and researcher at the University of Maryland School of Medicine, has developed an experimental vaccine in partnership with vaccine company Novavax Inc. that successfully protected mice against the MERS virus. Greffex, another vaccine company, has already worked with the US National Institute of Allergy and Infectious Diseases to develop a vaccine that triggers the production of antibodies—proteins that protect against the disease—in mice. Dr. Frieman and Greffex CEO John Price agree that funding and political will are the only barriers to the development of a MERS vaccine. According to Price, Greffex could develop a MERS vaccine candidate in less than a month with a sample of the virus, but they lack the funding to conduct clinical trials. Researchers have also struggled to obtain the needed information and materials—including samples of the virus—from scientists in Saudi Arabia. In the meantime, Frieman is working to test existing, approved drugs for the treatment of MERS, and has identified 27 drugs that have demonstrated potential in combatting MERS in a laboratory setting. At this year’s G7 summit, leaders of seven countries—including Canada, France, Germany, Italy, Japan, the United Kingdom, and the United States— pledged to advance research and development (R&D) for neglected tropical diseases and new antibiotics. The members of the G7 committed to supporting everything from basic research through the development of “easily usable and affordable drugs, vaccines and point-of-care [diagnostics].” The G7 Leaders' Declaration also endorses the WHO Global Action Plan on Antimicrobial Resistance and the WHO Global Observatory on Health Research and Development, highlighting the need for improved coordination of global health R&D. In a New York Times op-ed, Gregg Gonsalves and Mark Harrington, co-founders of the Treatment Action Group, reflected on lessons learned about the US Food and Drug Administration’s (FDA) drug approval process during the US HIV and AIDS epidemic. The article comes as Congress is considering the 21st Century Cures Act, a bill intended to advance medical breakthroughs, in part through FDA reform. The legislation includes several provisions to expedite the approval of drugs and medical devices based on what Gonsalves and Harrington consider to be “lower standards.” The authors assert that while innovative regulatory pathways—such as the Accelerated Approval Program—enabled early access to new HIV and AIDS drugs, pharmaceutical companies were still required to demonstrate the safety and efficacy of products before they entered the market. Additionally, in the case of preliminary approval, companies were expected to continue and complete clinical trials. To protect patient safety, Gonsalves and Harrington argue that such standards should be upheld, reminding Congress that those standards “paved the way for the development and approval of breakthrough drugs [that] have been proven to be effective and safe.” There are nearly 170 contraceptives products in the R&D pipeline, from discovery, through product development, to regulatory review. Researchers, advocates, funders, and procurement agencies can now find information about these products all in one place through Calliope, the Contraceptive Pipeline Database, a new resource developed by GHTC member FHI 360. Calliope includes information regarding the R&D stage, the partners, the active pharmaceutical ingredients, the delivery and duration, and the mechanism by which the technologies prevent pregnancy. The contraceptive pipeline is diverse, and includes vaccines, microbicides, implants intrauterine devices and balls, pills, and even microchips. The exchange was created to galvanize contraceptive R&D for low-resource settings through knowledge sharing and the facilitation of cross-sector partnerships.

The French pharmaceutical company Sanofi purchased a priority review voucher (PRV)—which entitles the owner to an expedited review of a future product by the US Food and Drug Administration (FDA)—for US$245 million last week. This particular sale was part of the Rare Pediatric Disease PRV, which was modeled after the Neglected Tropical Disease PRV—a program intended to incentivize research and development (R&D) for neglected diseases, as the market for drugs to treat these conditions is often limited. The voucher significantly expedites the FDA’s review process, from 10–12 months to 6–8 months. This voucher was awarded to Retrophin for approval of a drug to treat bile acid synthesis disorders, which are considered rare pediatric diseases. Only two vouchers have been awarded through a PRV program, the first of which was sold to Sanofi for $67 million and the second to Gilead Sciences for $125 million. Delegates from the World Health Organization’s (WHO) 194 member states approved a resolution at the World Health Assembly—the organization’s annual convening—to address the spread of antimicrobial resistance. The resolution establishes a global strategy to control and prevent the spread of drug-resistant infections, including through the R&D of new antibiotics. Under this new resolution, member states will be required to develop and implement national plans to combat antimicrobial resistance within the next two years. WHO Director-General Dr. Margaret Chan assured delegates at the World Health Assembly that the WHO will provide technical support to national governments as needed, stating “we are going to do our utmost to support you.” The status and progress of these efforts will be reported to the World Health Assembly in May 2017. Photo: World Health Organization The global action plan, presented by the WHO Secretariat during the World Health Assembly, called for improved surveillance; increased awareness; and adequate, sustainable R&D funding surrounding the growing threat of antimicrobial resistance. The plan notes the “serious market failure” for antimicrobial R&D, calling for new mechanisms to incentivize and accelerate the development of new antibiotics. Senators Patrick Leahy (D-VT) and Chuck Grassley (R-IA) recently introduced the bipartisan Patents for Humanity Program Improvement Act, which expands the Patents for Humanity program at the US Patent and Trademark Office (USTPO) to ensure small businesses can participate. Each year, USTPO identifies approximately ten products that have been patented through their office and that have since been used for humanitarian purposes, and provides the winners with a voucher for an expedited patent application, ex parte reexam, or ex parte appeal. The legislation would make the voucher transferable, which would encourage small businesses or individual researchers or inventors—who may not anticipate future patent applications or dealings with USTPO—to participate.

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.