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Drug development is a long and complex process. Estimates of the cost to develop a drug can range from $150 million to $1.3 billion up to the point of regulatory approval, and the process can take upward of a decade. In this guest post, PATH’s drug development program provides a step-by-step overview of what goes into each phase of drug development. The program’s investigational new drug for diarrheal disease, iOWH032 (currently in phase 2 trials), serves as an example. This is the first post in a three-part series. Break down a disease and find a promising agent At this stage, researchers examine the mechanisms by which a disease affects normal physiological processes, in order to determine which mechanism provides the most attractive target for treatment. In consultation with an international advisory board of clinicians, scientists, and public health experts, our team selected the CFTR chloride channel as the best target to combat the deadly dehydration caused by diarrhea. From 2007 to 2010, we partnered with private pharmaceutical companies Roche, Novartis, and BioFocus DPI to screen nearly 2 million molecules from their chemical libraries. Forty drug leads were identified for further research, and one, iOWH032, was selected for further development. Assess safety and biological activity in laboratory and animal studies Before a drug can be tested with healthy volunteers, scientists must first assess the safety and biological activity of the drug in a laboratory setting, according to US Food and Drug Administration (FDA) standards. From 2010 to 2011, our team conducted toxicology studies in several animal species and found iOWH032 to be safe, even at very high doses. Additionally, iOWH032 reduced cholera toxin-induced intestinal secretion in several animal models and in vitro. Submit your chemical and manufacturing data, preclinical test results, and the rationale and strategies for clinical studies After preclinical testing is completed, scientists are able to submit chemical and manufacturing data and preclinical test results, as well as the rationale and strategies for clinical studies, to the FDA in an Investigational New Drug (IND) application. On December 27, 2010, we submitted an IND for iOWH032, the first submission of an IND for a completely new chemical entity by a small nonprofit organization. We received rapid clearance by the FDA on February 4, 2011. Determine a compound’s safety and pharmacology in healthy volunteers With necessary ethical reviews completed and the IND granted by the FDA, drug developers can proceed to clinical trials in healthy volunteers. At this stage, clinician-scientists can begin to determine a compound’s safety and clinical pharmacology. Between 2011 and 2013, we partnered with Quintiles, a clinical research organization based in Kansas, to conduct two studies evaluating iOWH032’s safety and tolerability, as well as measuring the extent and rate of its absorption, distribution, metabolism, and excretion. The studies involved 92 healthy volunteers and concluded that iOWH032 was safe and well tolerated. No serious adverse events were reported. During 2013, we conducted a study in partnership with the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) to assess the pharmacokinetics, safety, and tolerability of iOWH032 in eight healthy Bangladeshi volunteers. Reports of the drug’s safety and tolerability, as well as the pharmacokinetic profile, were very similar to the results concluded from the studies of healthy American volunteers, and no serious adverse events were reported. Evaluate a compound’s effectiveness and side effects in cholera patients In phase 2 trials, a drug is evaluated for its effectiveness and potential side effects in patient volunteers. Beginning this year and continuing into 2014, iOWH032 is in phase 2 clinical trials. Ongoing studies are being conducted at icddr,b to assess the pharmacokinetics, safety, and efficacy of iOWH032 in patients with severe cholera. Verify a compound’s effectiveness and safety and confirm dosage in patient volunteers At this phase, researchers seek to verify a compound’s effectiveness and safety, in addition to confirming dose and schedule in patient volunteers. During this final step before FDA approval, researchers confirm previous findings in a larger population. Phase 3 can last from 2 to 10 years, and involve hundreds or thousands of patients across multiple sites. Submit a new drug application to the FDA Once phase 3 is completed, a New Drug Application (NDA) can be submitted to the FDA. Information on the chemical makeup and manufacturing process, pharmacology and toxicity of the compound, human pharmacokinetics, results of the clinical trials, and proposed labeling is provided. Once the NDA is approved, the drug can be marketed. Conduct post-marketing surveillance In phase 4 trials, drug developers conduct post-marketing surveillance, without major enrollment restrictions, to examine the risks and benefits of a new drug in a larger patient population. Phase 4 studies may be conducted to evaluate the long-term effects of a drug over an extended period of time in a larger group or to continuously discover more information about the drug, including benefits in other areas (beyond what is on the approved label). Photos: 1, 3, and 7, PATH Drug Solutions; 2 and 4, PATH/Patrick McKern; 5, 6, and 8, ©Jonathan Torgovnik.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. A potential malaria vaccine has shown promising results in early stage clinical trials, researchers announced this week. Bloomberg reports on efforts to develop the first vaccine for dengue fever. The Chinese Center for Disease Control and Prevention and Aeras have signed a memorandum of understanding to advance research and development for new vaccines to prevent tuberculosis. The University of Washington has received $9.6 million grant from the Department of Defense to continue work developing a diagnostic test for infectious diseases in low-resource settings. The US Food and Drug Administration (FDA) tentatively approved India-based pharmaceutical company Strides Arcolab’s HIV drug. Legislation recently introduced in the US House of Representatives would amend a five-year exclusivity provision for new combination drugs approved by the FDA. Think Africa Press examines how a new treatment for visceral leishmaniasis, under development by the Drugs for Neglected Diseases initiative, could help patients in Kenya.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. The US Agency for International Development (USAID) and partners recently announced nominees for the Saving Lives at Birth: A Grand Challenge for Development initiative. In related news, plans are “taking shape to merge two offices” at USAID to create an institute that would test and scale up “technologies and innovations to spark major development breakthroughs,” Devex reports. The Treatment Action Group and HIV-iBase have released the 2013 Pipeline report, which calls on leaders in global health, government, and research to commit to and coordinate efforts that will expedite access to effective diagnostic, treatment, and prevention tools. The Infectious Disease Research Institute (IDRI) and Zydus, India’s fourth largest healthcare group, will partner to develop IDRI’s visceral leishmaniasis vaccine candidate. An op-ed in The Guardian by Dr. Anurag Mairal, global program leader of Technology Solutions at PATH, examines the importance of public-private partnerships for global health. “Our nation’s research ecosystem is now in a precarious state as a result of federal policies and proposals that continue to undermine medical innovation,” John Edward Porter, chair of Research!America’s Board of Directions, writes about sequestration in a new op-ed.

  As we discussed yesterday, lawmakers in the House and Senate have been busy with several pieces of legislation that would fund global health and research efforts across the federal government. Our first post yesterday detailed implications for global health research and development (R&D) activities at the US Department of State and US Agency for International Development. Today, we provide highlights for other key agencies involved in global health R&D. Labor-HHS The Senate Appropriations Committee has approved legislation to fund the Labor, Health, and Human Services (HHS) account, which includes support for the National Institutes of Health (NIH) and the US Centers for Disease Control and Prevention (CDC). Currently, there is no House version of this bill—a hearing scheduled for last week was canceled—so while we don’t have those figures to compare funding levels with, we do know that the House allocation for this account is drastically lower than the Senate version. Lawmakers in the House and Senate have been busy with several pieces of legislation that would fund global health and research efforts across the federal government. including the DoD, CDC, FDA, and NIH. The Senate bill would fund the NIH at $30.9 billion, which is a welcome but small increase of $307 million over FY 2013. Many key institutes and centers—including the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Human Development, and the Fogarty International Center—were funded at levels higher than the final FY 2013 allocations but lower than the levels President Obama requested for FY 2014. One exception is the National Center for Advancing Translational Science, which received a total of $662.4 million under the bill—a boost in funding of $87 million over FY 2013. This includes a total of $50 million for the Cures Acceleration Network. The legislation would fund CDC at $6.9 billion, an increase of $681 million over FY 2013 and $300 million over the President’s request. This funding includes $391 million for the Center for Global Health, a significant increase of $46 million over FY 2013. The National Public Health Institutes received a $10 million allocation under the bill, which also included a large bump for polio eradication: $146 million versus the $131 million the President requested and the $116 million from FY 2013. The National Center for Emerging Zoonotic and Infectious Diseases was funded at $335 million, an increase of $44 million over FY 2013. FDA The House recently passed its appropriations legislation to fund the US Food and Drug Administration (FDA), providing the agency with $2.485 billion (not including income from user fees). This is roughly $20 million more than the agency received in FY 2013 and $40 million more than the President requested. Language was included in the bill that would ensure the FDA can review products for all neglected diseases, encourage the agency to “build stronger partnerships with global regulatory stakeholders, and strengthen its internal capacity to review products for neglected diseases.” Similar language was included in the Senate version of the legislation, which funds FDA at a higher level of $2.562 billion, or roughly $77 million more than the House version. Defense The full House passed a Department of Defense funding bill, in which the entire agency was provided with $513 billion. The bill would also provide $9.6 million for malaria vaccine development efforts, and welcome language is included in the bill report regarding the need for such a vaccine. The Senate Appropriations Defense subcommittee voted on its version of Defense funding yesterday, July 30th. We’re still waiting for the release of the accompanying bill report to determine any implications for global health R&D. As we pointed out yesterday, it’s clear that many global health R&D programs are being flat-funded year after year. If Congress is unable to reach a long-term budget deal, sequestration cuts will take effect again, further hampering efforts to develop urgently needed new technologies. Congressional policymakers could still reverse this trend by fully funding global health and health research programs through the FY 2014 budget conference later this year, as well as through negotiations around the impending debate on the US debt ceiling. However, with the difficult political climate, it’s unclear whether they will take advantage of this important opportunity. Links to other helpful analyses: American Association for the Advancement of Science Alliance for a Stronger FDA