News

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. The United Kingdom’s Department for International Development has announced it is investing £138 million—or approximately $215 million—over the next five years into nine public-private partnerships to support the development of new drugs, vaccines, insecticides, diagnostic tools, and microbicides. In the newest issue of Frontlines, the online magazine from the US Agency for International Development, the agency looks back at some of its most successful projects—several of which involved investments in innovation, research, and development. Belgian scientists have taken early steps toward the development of a new drug to treat sleeping sickness. Ahead of the upcoming United Nations General Assembly next month, Secretary-General Ban Ki-moon has released a report with updates on the Millennium Development Goals and next steps. The Global Post reports on an in-depth research project examining diarrheal disease in the developing world, which could be used to help develop new vaccines and other tools against childhood diarrhea.

Hing Sham, PhD, joined PATH recently as head of research and preclinical development for the Drug Development program. Hing has more than 30 years in the private pharmaceutical industry, where he led major projects for various diseases, including HIV, cancer, diabetes, and Alzheimer’s. In this guest post, Hing answers questions about the risks associated with drug development and the intricacies involved in bringing a drug to market. This is the second post in a three-part series on drug development. Q: Drug discovery and development is a long process. Estimates of the cost to develop a drug up to the point of regulatory approval can range from $150 million to $1.3 billion. Could you summarize drug development in just a few words? A: In a few words, drug development is not for the faint of heart! What I mean by that is drug development is one of the most complicated and high-risk businesses in the world. When you think about what we’re trying to do, which is basically to correct a physiological process so it functions the same way it would in a healthy individual, it’s very complex and riskier even than going to the casino. In drug development, from choosing the right target to successfully completing multiple phases of clinical trials to clearing regulatory hurdles, there are many things that can go wrong. Under the best circumstances, your success rate is around 20 percent. It’s definitely a worthwhile endeavor, but each new hurdle brings with it a new set of anxieties. Hing Sham, PhD, joined PATH recently as head of research and preclinical development for the Drug Development program. Credit: PATH/Elena Pantjushenko. Q: What is the most exciting part of drug discovery? A: For me, the most exciting moment is when the different puzzle pieces come together to form a clear profile of a potentially successful drug candidate. Before this can happen, you have to have already chosen the correct target to treat within the human body and then have chosen the right compound from thousands of possibilities to target that mechanism for the desired effect. In addition, you have to determine that the compound has gone through the right testing to ensure that it’s in the best position to clear clinical trials and other safety hurdles. When all of that begins to align for the first time, it’s very exciting. Q: One concept you’ve emphasized as inherent to successful drug development is the importance of “failing early.” What does it mean to fail early, and why is that a good thing? A: Failing early isn’t a new idea in the drug development industry, but it’s a term that’s gained popularity as philanthropic foundations have encouraged a shift to the left in the product development pipeline. It is important to answer core questions early to avoid spending resources on products that will not be able to move forward and will languish in the “valley of death,” the term for scientific discoveries that don’t fit the criteria for further development. Failing early doesn’t mean that a team is encouraged to fail. Instead, it means that when the data are discouraging, the team should accept that, and move on to more promising prospects. Q: Is it difficult to keep your judgment clear and make these tough calls? A: I think, even if the results indicate you’re heading in the wrong direction, the desire to see your efforts through is part of human nature. As a researcher, it’s tempting to come up with other experiments that could enhance your understanding of a drug, even though they aren’t necessarily critical to the core questions under investigation. Within a project, stakeholders must engage in rigorous debates to determine what the critical questions are for a project’s success. Making these determinations early on provides the best framework for evaluating a drug candidate’s promise at various stages of development. Q: What do you find most fulfilling about your work? A: After 30 years in the private pharmaceutical industry, I have an immense appreciation for what the private sector does in devoting resources to research for lifesaving therapies. Now with PATH, I feel I have the unique opportunity to bridge the best of the private and nonprofit sectors to tackle a tremendous need for efficacious drugs for diseases unique to poor countries. It’s fulfilling to know that our work is bringing the best science to bear on some of the world’s most challenging health issues.

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.