Book review of Allen Buchanan’s “Better Than Human” (published in Duke Magazine, Jan-Feb 2012)
Nonfiction, January 2012.
“In sports, it has become unfortunately common for athletes to use anabolic steroids and other drugs to improve their abilities. But in the workplace, what if your coworkers were using cognitive-enhancing pharmaceuticals and, as a result, your boss was considering firing you for poor performance? Further complicating the matter, what if you then felt compelled to take these medications but were distressed about potentially devastating side effects?
These are some of the ethical dilemmas raised by the growing use of enhancements, which are drugs and devices that can lift a user’s capabilities above normal human levels. Studies in healthy volunteers have demonstrated that various medications can impart cognitive benefits. When adult participants were kept awake for two consecutive nights, the sleep-disorder drug modafinil (brand name Provigil) significantly increased alertness and performance on cognitive tests….”
Upholding Standards: Should the FDA approve a new lupus drug with unclear benefits? (article in mckee.wordpress.com)
Nonfiction, December 2010. Update: Benlysta was approved by the FDA on March 9, 2011.
If you are one of the estimated 300,000 to 4 million patients in the US who suffer from lupus, you may feel excited about a drug called Benlysta (generically, belimumab). There is a need for better drugs to treat symptoms, reduce the use of other medications that can have imperiling side effects, and reverse disease progression. The US Food and Drug Administration (FDA) plans to decide whether to approve belimumab by December 9th.
For unknown reasons, in lupus the immune system attacks the body, leading to a chronic inflammatory disease. The illness can vary greatly for each patient and between patients. Flares can appear unexpectedly and with an unpredictable severity, several times a year. Symptoms often are “general” (fever, weight loss and fatigue) and organ-specific, including joint pain, skin lesions, kidney injury, and heart injury among others. In severe cases, a patient may die from kidney failure, severe infection, stroke or other causes.
A lupus diagnosis is no longer a death sentence. Sixty years ago, the 5-years survival rate was 40%, whereas since the 1980s it has been over 90%. This may have occurred as physicians learned to identify and treat the disease sooner or use medications “off label” to help patients. While the only FDA-approved medications for lupus are aspirin, prednisone and the anti-malarial drug hydroxychloroquine, some patients also find benefit from immune suppression drugs like cyclophosphamide and other glucocorticoids related to prednisone. Yet taking these medicines brings many side effects, often severe. They can include increased risk of severe infection, body weight increase and redistribution, rashes, eye cataracts, and increased risk of major cardiovascular illness including heart attack and stroke.
Enter the hope for belimumab. Its makers, Human Genome Sciences and GlaxoSmithKline, conducted two Phase 3 trials that each enrolled 800 to 900 patients, all of whom received standard of care medicines like prednisone. In addition, the patients either received placebo or belimumab. Trial researchers tracked patients’ symptoms to determine whether they responded to the drug.
Did the drug reduce lupus symptoms? In one trial with patients who were from Asia and Latin America, 58% of patients receiving the target dose of belimumab responded compared to 44% in the placebo arm. This difference reached statistical significance, meaning it was highly unlikely for these groups to have differed solely by chance. But in the second trial, with patients in the US, Canada and Europe, the improvement was smaller at 12 months (43% response compared to 34% with placebo) and disappeared by 18 months. In addition, patients of African-American or African heritage worsened with belimumab. In the first trial, 46% of these patients responded compared to 64% on placebo. In the second trial, it was 33% for belimumab versus 39% for placebo.
Was the drug safe? Of 2,133 patients treated, death was 1.8 times more likely for patients on belimumab (0.9% of patients) than on placebo (0.4% of patients), and this was a statistically significant result. 71% of patients treated with the drug got an infection (of any severity) compared to 67% of those receiving placebo. Serious infections were slightly more frequent with belimumab than placebo (6% of all patients in the Phase 2 and 3 trials, versus 5% for placebo).
Considering these findings, will the FDA approve the drug? On the one hand, some industry analysts have written, approval would encourage other lupus drug makers. Yet lowering the bar would only benefit short-term industry interests at the expense of patients. Difficult problems require innovation and perseverance. Perhaps suggesting it would not lower its standards, in a briefing to the FDA’s recent advisory panel, the agency raised several major criticisms of the belimumab results.
Yet surprisingly, the panel voted 13 to 2 in support of belimumab. Meeting minutes have not yet been released. Reuters quoted one panel member as saying, “The efficacy is mild, but I think there is a need for drug even with mild efficacy.” The FDA is not required to follow the panel’s recommendation, though several journalists have indicated it usually does. One additional variable is that the drug may cost $20,000 to $30,000 per year. While this is expensive, it is not nearly as expensive as some drugs for cancer or other rare diseases (see list here), though it would rack up costs as patients took it chronically.
One compromise is the FDA could approve the drug with restrictions. For instance, the drug might be permitted only for patients the drug helped, such as those of Caucasian heritage or with skin or musculoskeletal forms of the illness. Or it may be restricted to 12 months or less of continuous therapy. In a few weeks we will learn of the decision. Hopefully it will be made in the interest of patients first.
- Mayo Clinic overview of lupus
- Mayo Clinic overview on of glucocorticoid drugs
- UpToDate patient information on lupus
- Article on lupus epidemiology
- Articles on FDA panel backing Benlysta:
- FDA Arthritis Advisory Commitee 2010 meeting materials
- FDA and the clinical trial process for drugs seeking approval
- The clinical trials discussed above are BLISS-52 (HGS press release) and BLISS-76 (press release).
Frank Rijsberman of google.org: The global water crisis (article in mckee.wordpress.com)
Nonfiction. Co-authored with Saket Vora, January 2009. Update: Rijsberman is now Director of Water, Sanitation and Hygiene (WASH) at the Bill & Melinda Gates Foundation.
On Dec. 4th, Frank Rijsberman of Google.org gave a talk about the global water crisis. Now a Program Director for water issues, Rijsberman has more than 15 years’ experience in water development, most recently being the former director of the International Water Management Institute based in Sri Lanka. He has also been a water resources engineer, co-founded a water consulting group, and built tools to analyze water usage. The talk began with a discussion how the water crisis affects us despite so many of the truly pressing problems happening on the other side of the globe, then moved into discussing the specific types of crises associated with water, and a more detailed look at water scarcity issues. Rijsberman then used four vignettes from Africa and south Asia to highlight the issues discussed before.
Rijsberman described how the water crisis is already relevant to Americans. Approximately 3 billion people live in areas with poor drinking water. Two-thirds of the world population is projected to be experiencing water scarcity by 2028. Given the talk was at Stanford, he also highlighted the water shortage California is already experiencing. Worldwide water-related diseases account for 82 million disability-adjusted life years (DALYs) lost. DALYs is a metric that attempts to capture the health and economic burden of disease in a population. Many water-related diseases may not be fatal, but they can render a person unable to work and thus have severe economic impact to both a household and an economy. Sub-Saharan Africa accounts for 25 million of these DALYs and also for 769,000 child deaths per year from poor water quality. Touching briefly on the future impact of climate change, he mentioned that the main problem with global warming will be increased variability of precipitation, leading to stronger wet seasons or longer droughts. Paraphrasing another scientist he thus mentioned, “if climate change is all about energy, then climate adaptation will be all about water.”
The next major point was that the water crisis is about food, not drinking water. Food requires approx 70X the volume of daily household needs. As a rule of thumb, every calorie (kcal) of food produced requires one liter of water. He cited ballpark figures we quickly jotted down:
|Type of water use||Amount (liters)|
|drinking daily use||2-5|
|household daily use||20-400|
|water to produce 1kg of grain||1,000 of ET (evapotranspiration)|
|water for a vegetarian’s daily food||2,600 of ET|
|water for a meat-eater’s daily food||5,400 of ET|
Earlier this year, I measured my average water use and found it ranged from 100 - 200 L/day. To illustrate the water intensity in making food products, Rijsberman described the water used to produce a can of Coca Cola. The water in the cola drink is almost nothing compared to the water required to grow the corn for sugar, process the aluminum (extracting from bauxite ore, processing, and cleaning), and provide cooling for energy during manufacturing.
Removing another potential myth, Rijsberman described two types of water scarcity: physical and economic. Physical water scarcity means there is no access to water. Economic water scarcity means there is water nearby but people lack the infrastructure, governance, accountability, and economic systems to utilize the water sustainably. Rijsberman showed several maps showing environmental water stress using the widely used Falkenmark indicator, which is a measure of renewable water resources per capita per year. Speaking to FR afterward, he said that basically there is no place in the world where physical scarcity is the primary problem. (Even when river basins are drying up there may be other ways to capture available water, for instance through rainfall storage or groundwater access). The true problem is economic scarcity.
To again set the stage for the broad audience, he shared ballpark numbers for the cost of different types of water use.
|Product||Cost per cubic meter (1000L or 250 gal)|
|retail H2O (e.g., Dasani)||≤$10,000|
|Bulk bottled H2O (5-gal tanks)||$100-200|
|Tap||$1-2 (Califoria 2006: $0.85)|
|Irrigation||$0.01-0.02 (≥$12-24 per AF)|
Note on conversions: 1 acre-foot (AF) = (42,560 ft^2)(ft)/(3.28 ft/m)^3 ≈ 1,206 m^3. My friend David Zetland at Aguanomics showed me the “1-2-3-4″ memory trick: 1AF ≈ 1,234 m^3. 1 m^3 = 264 gal or ≈250 gal per Dr. Rijsberman.
Within the overall challenge of economic water scarcity, Rijsberman argued that there are 2 distinct crises: the service crisis and the resource crisis. The service crisis arises when a lack of infrastructure is unable to provide affordable drinking water to a population. This problem is exacerbated by the high capital cost of water purification and distribution systems needed to address the needs of growing populations. Urban areas are struggling to keep up with the influx of people from rural areas, and those who continue to reside in rural areas face distribution and transport difficulties. A variety of private enterprises have arisen to address this problem. Rijsberman highlighted the town of Afuaman, Ghana where WaterHealth International invested $50,000 for a facility that processes river water and purifies it with UV light. It sells 5 gallon jugs for $0.01/gal. In contrast, water tankered into the town is sold at $0.0375/gal and bottled water for $0.38/gal. There is an on-going debate about the role of these private water providers — should people be making profit on selling a fundamental life necessity like water, particularly to people who are among the poorest in the world? If so, where does one draw the line in terms of profit margins or costs to consumers?
The resource crisis was briefly touched upon, primarily highlighting the tensions that arise when attempting to partition a scarce resource between industrial, agricultural, and drinking needs in a community. Rijsberman discussed the idea of a ‘water footprint’, a measure analogous to a carbon footprint that tries to measure the total amount of water used to make goods available to people. Waterfootprint.org has more on this measure, with case studies and region analysis. This served as a segue into a vignette about Godino village, Debra Zeit, Ethiopia. People in this rural community have been forced to resort to a rudimentary form of farming and living. A woman fills a 5 gallon tank with dirty water and treks miles back to her village. A farmer works with his bare hands to shape and irrigate his fields. IWMI has worked to install $50 treadle pumps that can boost a farmer’s annual income by $100-$200. Here’s the punchline: within a 30 minute drive of this setting, there is an enormous greenhouse facility on the scale of football fields. Constant temperature and computer-controlled watering. Dutch roses and flowers are grown then exported to the world’s largest flower auction. An oasis in the middle of hardship. We could sense a feeling of disgust in the audience, and questions of social justice and of resources misallocation quickly jumped to mind. But Rijsberman asked the audience a question: if you were a parent of a teenager looking for a job, what would you tell them? To stay on the meager family farm or to go work at the very greenhouse that is exacerbating the farm’s poor condition? No easy answers.
Rijsberman showed a vignette about wastewater in Hyderabad, India then moved to Q&A. He was asked what he thought about the privatization of water, to which he answered it was the wrong question to ask. What’s important is the decentralization of the water distribution method so it remains local, he said, and ensuring transparent and effective regulation of public/private enterprises. Involving the community when organizing and implementing water delivery projects is critical for impact. Sanitation is another issue that came up. It is very difficult to get people to pay for sanitation. Too often it comes down to a feeling that “it is someone else’s problem.” Rijsberman showed examples of wastewater being preferred (indeed, it costs morethan clean water) for crop irrigation in parts of South Asia and Africa because the wasterwater contains nutrients for the crops. 90% of the vegetables in Africa and 26% of the vegetables in Pakistan are produced with wastewater. Of course, there are serious health risks that arise when using contaminated wastewater to grow vegetables, but one point is that if wastewater has real value, then can revenues from it be used to pay for sanitation?
Like many of the challenges facing international development and poverty, there is no silver bullet to solving the water crisis. There were questions regarding technological solutions to this, but technology alone can only do so much. Expanding the discussion beyond clean drinking water to address agriculture and food needs was particularly welcome, as was truly establishing how the global water crisis has real local impacts, no matter where you live. With globalization, people on opposite sides of the world can tangibly affect the daily lives and well-being of people (as seen with the Dutch flowers and water footprint). As we struggle to determine how to use the scarce resource that is water in the closed system that is our planet, a phrase by Rijsberman comes to mind: “Every drop of water has a purpose.”
For more about what Frank Rijsberman discussed at this talk, we encourage you to read a Boston Review article he wrote titled Every Last Drop. For a good overview of global agricultural water challenges, we suggest the FAO’s 2007 “Water for food, Water for life” summary [pdf].