Faster access to new drugs can save countless lives and end needless suffering
Deaths from an approved drug become a top story for the nightly news and can lead to Congressional inquiries. Avoiding such negative publicity is the overriding goal of the Food and Drug Administration (FDA). The resulting extreme tunnel focus on safety causes delayed access to innovative drugs, which in turn causes millions of people to suffer and many to die needlessly.
When drug development, testing, and market access to drugs are viewed as a system, it is clear the appropriate system goal should be better drugs, sooner, at lower cost. However, “sooner, at lower cost” is ignored by FDA while it demands ever more testing. Today, a pharmaceutical company spends ten years in clinical testing for a new drug in hope of securing FDA approval. The total cost of an approved drug is about a billion dollars.
The nightly news misses the fact that FDA itself is the bottleneck in the system and fails to report that the result is an enormous invisible graveyard of those who were, are, and will be denied access to new drugs.
Consumer choice would break FDA’s monopoly on access to new drugs. That is the way to turn this problem into an opportunity. The core idea, which should appeal to Republicans, Democrats, and Independents alike, is that we need to be free to make our own informed decisions about whether to use not-yet-FDA-approved therapeutic drugs – that is, new drugs that have successfully passed safety trials, generated preliminary efficacy data, and may offer us the opportunity to improve our health or even save our life. I call this “Free To Choose Medicine.”
Consider how Free To Choose Medicine would have helped those with advanced prostate cancer, which kills 30,000 men every year. Many of those patients literally marched to Washington to rally against FDA’s excruciatingly slow process to approve Provenge, a strikingly innovative cancer vaccine that triggers the body’s natural immune defenses. Patient advocacy groups called for immediate access to Provenge. One memorable advertisement by the advocacy groups was headlined, “Dysfunction at the FDA: Prostate Cancer Victims Face Needless Suffering and Premature Death.”
FDA, with its habitual arrogance and seeming invincibility, is accustomed to ignoring the voices of patients, and it ignored, for many years, the demands of these men.
FDA Will Never Reform Itself
Henry Miller, M.D., a physician, molecular biologist, and public policy analyst who formerly held high-level positions within FDA, gives us his first-hand account of FDA pressures and incentives:
In the early 1980s, when I headed the team at FDA that was reviewing the NDA [New Drug Application] for recombinant human insulin … we were ready to recommend approval a mere four months after the application was submitted. … With quintessential bureaucratic reasoning, my supervisor refused to sign off on the approval – even though he agreed that the data provided compelling evidence of the drug’s safety and effectiveness. “If anything goes wrong,” he argued, “think how bad it will look that we approved the drug so quickly.”1
Dr. Miller’s devastating account of FDA decision-making is Exhibit One for the case that FDA is a dysfunctional system. The consensus opinion of economists who have studied the impact of the steady trend of increasing FDA demands for ever-more expensive and time-consuming clinical trials is that the cost to society has far exceeded the benefit. (See www.fdareview.org.)
A system that involves people is ineffective when incentives are misaligned with goals. Consider, for example, FDA’s “compassionate use” program. This is a program for people who have a life-threatening illness and for whom approved drugs are of little use. The more promising a new developmental drug is and the more serious an illness is, the more motivated patients are to gain access via compassionate use and avoid clinical trials. But there is little incentive for FDA to advertise or expand this program, since it competes with FDA’s primary motive, which is to encourage patients to enroll in clinical trials.
What FDA does want is for the public to accept without question that FDA’s role is to provide “safe and effective drugs.” But no drug is 100 percent safe. Even aspirin can lead, especially in elderly people, to hospitalization and death due to gastrointestinal bleeding and perforation. The simplistic slogan of safe and effective drugs diverts attention away from the basic tradeoff issue facing FDA: More extensive and hugely expensive testing may reduce the probability of unanticipated adverse side effects from an approved drug, but at the same time also greatly increases drug costs to consumers and, most importantly, causes suffering and premature deaths from delayed access. That’s the unavoidable tradeoff situation that is better handled by Free To Choose Medicine.
My proposal for Free to Choose Medicine is illustrated in Figure 1.
Figure 1 Dual Tracking
On one track, a new drug continues with conventional FDA clinical trials with the goal of securing FDA approval. On a new, separate track – the Free To Choose Track, which is independent of FDA – patients advised by their doctors make informed decisions to contract with a drug developer to buy a not-yet-approved drug. The drug developer would need to elect to place the drug on the Free To Choose Track, and that drug must have passed the midpoint of its Phase II testing so there would be an early indication of risk and effectiveness. Patients who opt for the Free To Choose Track could gain quicker access to new drugs – by five years or so – compared to waiting for possible FDA approval.
Instead of the current one-size-fits-all regulatory straitjacket that assumes everyone is equally risk-averse, patients could express their own unique preferences for risk, guided by their doctors’ and their own judgments about pain, the limited ability to work or perform daily chores, and the opportunity for health improvement – decisions only they can make. Patients could elect to use only approved drugs, which are very safe. No one is forced to accept less-safe drugs.
Creating a Tradeoff Evaluation Database
For us to be able to judge if the benefit from a new drug exceeds the benefit from an approved drug and is worth the risk – i.e., for us to be informed well enough to be able to evaluate the tradeoff – we and our doctors would need relevant, up-to-date information. Under my proposal, that information would be accessible on the Internet through a Tradeoff Evaluation Database (TED), as shown in Figure 2.
Figure 2 Tradeoff Evaluation Database (TED)
Legislation to implement Dual Tracking should specify that participation in the Free To Choose Track requires not only that doctors input treatment results to TED, but also that patients permit doctors to transmit the patient’s genetic and biomarker information to TED. Over time, this would create a treasure trove of public data that would greatly benefit pharmaceutical research.
Drug developers would be unlikely to make new drugs in clinical testing available through a Free To Choose Track if they could be held liable for all side effects even if they were not negligent in developing, testing, or manufacturing. Consequently, as part of a Free To Choose Medicine Act, Congress would adopt legislation permitting patients to waive their right to sue drug developers under strict product liability as long as developers do not provide false or misleading information.
At no charge, a government-operated TED would provide the information needed to make informed decisions about what is in patients’ best interests. Private-sector companies (e.g., Google, Microsoft, IBM, and such) would have a profit incentive to sell customized “consumer reports” that would further help patients and doctors. Consumer reports could pinpoint subsets of patients who are most and least likely to benefit, forecast the probability of FDA approval, and provide head-to-head comparisons of Free to Choose drugs against relevant FDA-approved drugs.2
TED would transfer knowledge (and power) to doctors and patients. This could disrupt enrollment in those clinical trials where knowledgeable doctors judge the drug to be tested as superior to approved treatments. The proper response from FDA should be to develop more innovative testing procedures that avoid unethical clinical trials and give top priority to today’s patient needs.3
Before and during Phase III testing, TED would make public a vast amount of clinical trial and observational data. Some drugs would show strikingly effective treatment results compared to FDA-approved drugs. Then, many knowledgeable doctors may object to enrolling their patients in Phase III randomized control trials on the ethical grounds of not wanting to subject their patients to the risk of receiving an inferior drug or useless placebo.
In this new environment, the formerly invisible costs of suffering and death due to delayed access to new drugs would become much more visible. Heightened public awareness of the opportunity costs would make things increasingly uncomfortable for FDA. Contributing to this pressure would be the lack of insurance coverage for the new drugs that are in high demand via the Free To Choose Track when they appear to be delivering significant health improvements.
Most private health insurance contracts cover only FDA-approved drugs. Lack of FDA approval could keep people with less financial means from obtaining the life-improving or life-saving drugs accessible via the Free To Choose Track. This is not a situation Americans would want, and we would pressure FDA to get more engaged with the needs of all patients.
One way to help FDA respond is for the Free To Choose Medicine Act to allow the agency to grant conditional approval for a new drug based on a combination of results from clinical trials and Free To Choose Track use. To maintain conditional approval, the developer would have to agree to complete Phase III trials and obtain conventional FDA approval within a reasonable time.
Change Attuned to the Future
There already is a segment of the medical marketplace where consumer choice is much less restricted. Off-label drug use occurs when doctors write prescriptions to be used in ways for which the drugs were not FDA-approved. A leading researcher in the treatment of breast cancer noted, “If I had to use drugs for their approved uses only, half my patients would be dead.”4
Off-label drug use is a window into an environment where things happen to best serve today’s patients. The widely acknowledged success of unregulated, off-label prescription use is consistent with expectations that doctors would actively use TED in the future for the benefit of their patients.
We need a drugs-to-patients system that can adapt to a future with an accelerated pace of medical innovation, coupled to the widespread advancement of personalized medicine. Diagnostic testing will match patients according to their genetic makeup with drugs that are much more likely to work and to have fewer adverse side effects. In this environment, early access becomes more and more beneficial over time. Dual Tracking would accommodate early access as well as dramatically speed up the delivery of medical advancements.
With the Free To Choose Track, a new drug showing strongly positive results would lead to a surge in use by patients with diverse characteristics that more accurately reflect the general patient population of drug users than do the patients enrolled in FDA’s randomized controlled trials. Consequently, upon receiving FDA approval, drugs would have a more reliable safety profile if they were used by patients on the Free To Choose Track. Consumers who choose to use only approved drugs would benefit from the voluntary decisions of those willing to accept more risk in exchange for early access.
A quite plausible forecast is that prescription drug prices would drop substantially after feedback about how well patients do when they opt to make their own choices for approved versus not-yet-approved drugs. Such feedback would be expected to compel FDA to radically streamline its testing process, thereby providing a major reduction in regulatory costs for drug developers.
To sum it all up, Free To Choose Medicine would provide faster access to new drugs, save countless lives, and end needless suffering. It would put us on a competitive path that both lowers prescription drug prices and advances innovation – exactly opposite of a price control path to lower drug prices that some health care reform advocates are pushing. Their option would seriously reduce long-term innovation.
Passage of a Free To Choose Medicine Act would be a defining moment for America – a directional change from today’s trend of increasing litigation and regulation – a stake in the ground that control of medical decisions belongs, first and foremost, with individual patients and their doctors, and not the government. It deserves a chance.
Bartley J. Madden is the author of Free To Choose Medicine.
1. Henry I. Miller, To America’s Health: A Proposal to Reform the Food and Drug Administration (Stanford, CA: Hoover Institution Press, 2000), 41-42.
3. “Types of Randomized Controlled Trials,” Chapter 2 in Alejandro R. Jadad and Murray W. Enkin, Randomized Controlled Trials (Malden, MA: Blackwell Publishing, 2007, 2d edition), 12-28. Scott Gottlieb, “Improving Access to Life-Saving Medicines through Modernization of the Regulatory Review Process,” presentation to the Food and Drug Law Institute’s Colloquium on Access to Unapproved Drugs, February 27, 2007 (unpublished).
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In the early 1990’s an extreme form of isolation emerged, where young Japanese people seclude themselves in their homes for months or even years at a time. Attempts to establish the prevalence of the phenomenon suggested over 1 million Japanese people could have hikikomori, but some researchers believe the actual number may be higher.
People with hikikomori often have symptoms of anxiety and depression and unusual sleep patterns. The official definition (sidebar below) includes complete home isolation, but most psychiatrists and researchers I encountered in Japan use a working definition that ranges from complete seclusion to going out every day but having no friends or jobs. Patients tend to sleep during the day, and at night they watch TV, play computer games, and read manga (comic books). They often eat alone in their bedrooms and do a great deal of internet chatting, but have very little face-to-face communication with others.
In rare but highly publicized cases, some of these people have committed suicide and even murder. In my experience, people with hikikomori mostly only seek medical help when they have no other choice, such as when their house is sold, their parents pass away or they run out of money.
The earthquake, tsunami and aftershocks could push thousands of people with hikikomori who had been previously living under the radar into the light, seeking help for the first time ever. This stands as a unique problem in comparison to other disasters such as those in Haiti and New Orleans.
And while it’s not clear exactly what causes hikikomori, traumatic events such as bullying, failing a test or not getting a job are often reported as triggers. The recent crises in Japan will cause psychological trauma for a variety of reasons, including the death of loved ones, the loss of entire towns, the ongoing nature of the disaster in the form of aftershocks and radiation-related problems. In addition, the crises will further erode young people’s ability to find gainful employment.
These two factors, in my opinion, will make it likely that young people in Japan who were on the brink of isolating themselves, and still have the financial means to do so, will shut themselves off from the rest of the world, creating new cases of hikikomori.
It’s not clear why this extreme form of social isolation has shown up in Japan, but several factors may be at least partially responsible. There is still a strong stigma regarding mental illness in Japan, which may cause sick people to hole up rather than seek help. Also, in Japanese culture, rest is considered a reasonable treatment for most mental illnesses. Many people with ADHD and depression I saw in Japan would try staying at home and resting for a few weeks before seeing a doctor. One researcher also suggested that hikikomori could be a reaction to the Japanese cultural emphasis on speed, efficiency, and punctuality.
A changing job market may also be contributing to the problem. Before the Japanese stock market collapsed in 1990, it was generally believed that a person would graduate high school or university, interview with one company, get hired and move up the corporate ladder in the same organization until the day they retired.
Hikikomori literally means “withdrawal” in Japanese and is used both as a noun and as an adjective. Though there are differing opinions as to the precise nature of hikikomori, Japan’s Ministry of Health, Labor and Welfare uses the following definition:
1. The person does not take part in society and is shut in his or her home for at least six months.
2. The person does not have any intimate relationships other than with family members.
3. The withdrawal is not a symptom of “other psychotic disorders.”
4. Social withdrawal: not taking part in social activities, school or work.
Since the crash, lifetime employment at an early age is no longer guaranteed, and young adults often interview at several companies and do not get a position immediately. Many times their parents react as they would under the old system and treat it as a major problem, causing the young adult to feel a great deal of shame. When these families are affluent and can support a reclusive child, it can lead to or exacerbate hikikomori.
While more than 200 English newspaper and magazine articles have been written about hikikomori since the early 1990s, there are only about 10 reports in the scientific literature in English. However, it’s my observation by interviewing patients, psychiatrists and researchers in Japan that despite the paucity of published research, hikikomori is a widespread problem that has ballooned in the last five years.
The prospect of acknowledging a new psychiatric disorder such as hikikomori is often met with skepticism in the psychiatric community, especially when reports are widely made in the media before scientific research is published. However, this was also the case with seasonal affective disorder and postpartum depression, which are now formally recognized in the Diagnostic and Statistical Manual of Mental Disorders.
Regardless, hikikomori should be considered as an important factor in any effort to help improve the mental health of people in Japan, a country that even before the current situation had one of the highest suicide rates in the world.
Given that the earthquake and its aftermath will likely bring pre-existing cases of hikikomori to clinical attention for the first time, and cause brand new cases as well, Japan will face an unprecedented need for psychiatric services, far more than would be expected in similar crises in other countries.
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Radiation from Japan has been detected in drinking water in 13 more American cities, and cesium-137 has been found in American milk—in Montpelier, Vermont—for the first time since the Japan nuclear disaster began, according to data released by the Environmental Protection Agency late Friday.
Milk samples from Phoenix and Los Angeles contained iodine-131 at levels roughly equal to the maximum contaminant level permitted by EPA, the data shows. The Phoenix sample contained 3.2 picoCuries per liter of iodine-131. The Los Angeles sample contained 2.9. The EPA maximum contaminant level is 3.0, but this is a conservative standard designed to minimize exposure over a lifetime, so EPA does not consider these levels to pose a health threat.[UPDATE: The FDA’s Derived Intervention Level for iodine-131 in milk is much higher: 4700 picoCuries per liter.]
The cesium-137 found in milk in Vermont is the first cesium detected in milk since the Fukushima-Daichi nuclear accident occurred last month. The sample contained 1.9 picoCuries per liter of cesium-137, which falls under the same 3.0 standard.
Radioactive isotopes accumulate in milk after they spread through the atmosphere, fall to earth in rain or dust, and settle on vegetation, where they are ingested by grazing cattle. Iodine-131 is known to accumulate in the thyroid gland, where it can cause cancer and other thyroid diseases. Cesium-137 accumulates in the body’s soft tissues, where it increases risk of cancer, according to EPA.
Airborne contamination continues to cross the western states, the new data shows, and Boise has seen the highest concentrations of radioactive isotopes in rain so far.
A rainwater sample collected in Boise on March 27 contained 390 picocures per liter of iodine-131, plus 41 of cesium-134 and 36 of cesium-137. EPA released this result for the first time yesterday. Typically several days pass between sample collection and data release because of the time required to collect, transport and analyze the samples.
In most of the data released Friday the levels of contaminants detected are far below the standards observed by EPA and other U.S. agencies.
But the EPA drinking-water data includes one outlier—an unusually, but not dangerously, high reading in a drinking water sample from Chatanooga, Tennessee.
The sample was collected at the Tennessee Valley Authority’s Sequoyah nuclear plant. A Tennessee official told the Chatanooga Times last week that radiation from Japan had been detected at Sequoyah but is “1,000 to 10,000 times below any levels of concern.” The 1.6 picocures per liter reported by the EPA on Friday is slightly more than half the maximum contaminant level permitted in drinking water, but more uniquely, it is many times higher than all the other drinking water samples collected in the U.S.[UPDATE: EPA released new data Saturday revealing higher levels than reported here in Little Rock milk and Philadelphia drinking water]
The EPA released this new data through a new interactive open-data system it quietly launched on the EPA website Wednesday. The new interface is to be regularly updated, replacing EPA’s periodic news releases and pdf data charts. Here are more details of the data released Friday:
Radioactive Iodine-131 was found in drinking water samples from 13 cities. Those cities are listed below, with the amount of Iodine-131 in picocuries per liter. The EPA’s maximum contaminant level for Iodine-131 in drinking water is 3 picocuries per liter.
- Oak Ridge, TN collected 3/28: 0.63
- Oak Ridge, TN collected at three sites 3/29: 0.28, 0.20, 0.18
- Chatanooga, TN collected 3/28: 1.6
- Helena, MT collected 3/28: 0.18
- Columbia, PA collected 3/29: 0.20
- Cincinatti, OH collected 3/28: 0.13
- Pittsburgh, PA collected 3/28: 0.36
- East Liverpool, OH collected 3/30: 0.42
- Painesville, OH collected 3/29: 0.43
- Denver, CO collected 3/30: 0.17
- Detroit, MI collected 3/31: 0.28
- Trenton, NJ collected 3/31: 0.38
- Waretown, NJ collected 3/31: 0.38
- Muscle Shoals, AL collected 3/31: 0.16
In the data released Friday, iodine-131 was found in rainwater samples from the following locations:
- Salt Lake City, UT collected 3/17: 8.1
- Boston, MA collected 3/22: 92
- Montgomery, Alabama collected 3/30: 3.7
- Boise, ID collected 3/27: 390
As reported above, the Boise sample also contained 42 pC/m3 of Cesium-134, and 36 of Cesium-137.
In the most recent data, iodine-131 was found in air filters in the following locations. In the case of air samples, the radiation is measured in picoCuries per cubic meter.
- Montgomery, AL collected 3/31: 0.055
- Nome AK collected 3/30: 0.17
- Nome AK collected 3/29: 0.36
- Nome AK collected 3/27: 0.36
- Nome AK collected 3/26: 0.46
- Nome AK collected 3/25: 0.26
- Juneau AKcollected 3/26: 0.43
- Juneau AK collected 3/27: 0.38
- Juneau AK collected 3/30: 0.28
- Dutch Harbor AK collected 3/30: 0.14
- Dutch Harbor AK collected 3/29: 0.11
- Dutch Harbor AK colleccted 3/26: 0.21
- Boise, ID collected 3/27: 0.22
- Boise, ID collected 3/29: 0.27
- Boise, ID collected 3/28: 0.32
- Las Vegas NV collected 3/28: 0.30
- Las Vegas, NV collected 3/30:: 0.088
- Las Vegas, NV collected 3/29: 0.044
No other types of isotopes were found in the most recent data from air samples, even though EPA is also on the lookout for barium-140, cobalt-60, cesium-134, cesium-136, cesium-137, iodine-132, iodine-133, tellurium-129, and tellurium-132.
In older samples, isotopes of cesium and tellurium were found in Boise; Las Vegas; Nome and Dutch Harbor; Honolulu, Kauai and Oahu, Hawaii; Anaheim, Riverside, San Francisco, and San Bernardino, California; Jacksonville and Orlando, Florida; Salt Lake City, Utah; Guam, and Saipan on the Marina Islands.
Some of these locations had not been previously reported in EPA news releases.
The EPA has said it will continue to monitor radiation levels in air, precipitation, drinking water, and milk even if the budget impasse shuts down the government next week.
There is more discussion of maximum contaminant levels and health concerns in the related links below and their associated comments:
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Radiation from Japan rained on Berkeley, California, during recent storms at levels that exceeded drinking water standards by 181 times. A rooftop water monitoring program managed by the University of California at Berkeley’s Department of Nuclear Engineering detected substantial spikes in rain-borne iodine-131 during those torrential downpours. The levels exceeded federal drinking water thresholds, known as Maximum Contaminant Levels — or MCLs — by as much as 181 times or 18,100%. Iodine-131 is one of the most cancer-causing toxic radioactive isotopes spewed when nuclear power plants are in meltdown. It is being ingested by cows, which have begun passing it through into their milk and radioactivity has been detected. [Multiple Sources]
Specific Scientific Data
The iodine-131 level in the rainwater sample taken on the roof of Etcheverry Hall on the campus of UC Berkeley on March 23rd, 2011, from 9:06-18:00hrs Pacific Daylight Time (PDT) states radioactivity levels at 20.1 Becquerels per Litre (Bq/L) = 543 PicoCuries per Litre (pCi/L). The federal maximum level of iodine-131 allowed in drinking water is 3 pCi/L or 0.111 Becquerels per Litre. The sample exceeded the federal guidelines for drinking water by 181 times. The UC Berkeley researchers also discovered trace levels of iodine-131 and other radioactive isotopes, believed to have originated in Fukushima, in commercially available milk and in a local stream within California. [UC Berkeley]
No Official Data Yet
Three weeks after the Fukushima nuclear power plant began spewing radiation into the world’s air, the US government has still not published any official data on nuclear fallout from the Fukushima meltdown. The amount of iodine-131 or other radioactive elements that have fallen as precipitation or made their way into milk supplies or drinking water has not yet been fully revealed. Scientists say an absence of federal data on the issue is hampering efforts to develop strategies for preventing radioactive isotopes from contaminating the nation’s food and water. [The Bay Citizen, San Francisco]
Fukushima radiation is blanketing most of the United States and Canada according to the data and visuals published regularly by the The Norwegian Institute of Air Research. The risks of that radiation falling with rain, have been downplayed by US government officials and others, who say its impacts are so fleeting and minor so as to be negligible. Nonetheless, radiation falling with rain can cover grass that is eaten by cows and other animals. It can also fall on food crops or contaminate reservoirs that are used for irrigation or drinking water. [Norwegian Institute of Air Research or NILU]
Food and Water Watch
Food and Water Watch — the nonprofit Non-Governmental Organisation (NGO) based in Washington, DC — sent a letter to President Barack Obama and members of his cabinet and Congress a few days ago urging the US federal government to improve its monitoring of radiation in agricultural land and food in the wake of the Japanese tragedy. The letter from “Food and Water Watch” states: “The three agencies that monitor almost all of the food Americans eat … have insisted that the US food supply is safe . . . the agencies, however, have done very little to detail specific ways in which they are responding to the threat of radiation in food.”
EPA and FDA
The federal Environmental Protection Agency (EPA) states in its April 3rd advisory, “As the Nuclear Regulatory Commission has said, we do not expect to see radiation at harmful levels reaching the US from damaged Japanese nuclear power plants.” The US Food and Drug Administration (FDA), which regulates food safety, has referred questions about potential milk contamination to the EPA, which is taking the lead on testing dairy products for radiation. Early last week, the EPA said it expected to release results of tests for radioactivity in rain and snow within a day or so. Just before the weekend, three days after making that pledge, EPA officials repeated the same statement and said the data would likely be released over the weekend or early this week. So far that data set has not been released. [EPA]
Potentially cancer-causing radiation from Fukushima has been encircling the world, traveling quickly on jet streams high in the atmosphere and falling with precipitation like rain and snow. It is already being detected in air, water and milk in some parts of the United States by local and state agencies. For example, San Francisco rain water radiation levels exceeded federal drinking water thresholds by as much as 181 times recently. A radioactive isotope, such as iodine-131, is supposed to have a half-life of eight days. This is inferred to mean that it breaks down quickly, and it quickly dissipates in the environment. However, the 8 day half-life can be a misnomer because radioactive iodine can really persist in the environment for many months and has a 100 day biological half-life once inside the human body.