The Strange Fate of Eben Byers

Fall Guy

In November 1927, a wealthy industrialist named Eben Byers was returning from the annual Harvard-Yale football game aboard a special chartered train. Yale won the game 14-0, and Byers was a Yale alumnus. It’s not clear whether the celebratory atmosphere aboard the train (or Byers’s reputation as a ladies’ man) had anything to do with it, but sometime during the trip he fell out of his upper sleeping berth and injured his arm. The injury interfered with Byers’s golf game and his love life. He visited on doctor after another, but no one could ease his pain. Then a physician in Pittsburgh suggested he try Radithor, a patent medicine (which consisted of little more than the element radium in a distilled water solution).

Radithor was a product of the Bailey Radium Laboratory of East Orange, New Jersey, found by one “Dr.” William Bailey, a Harvard dropout who falsely claimed to have a medical degree from the University of Vienna. In 1915 he had served time in jail for mail fraud. A few years later, after a stint peddling strychnine, the active ingredient in rat poison, as an aphrodisiac under the brand name Las-I-Go For Superb Manhood, he began selling Radithor as “Pure Sunshine in a Bottle.” He claimed it would cure more than 150 different ailments.

Hot Stuff

Drinking radioactive water to improve health may sound crazy today, but in the 1920s, when much less was known about radiation, it seemed to make sense. People had long wondered what gave natural hot springs their supposed healing properties. When the waters were found to be mildly radioactive due to the presence of dissolved radon gas in t he water (an hour’s soak in a hot spring exposed the soaker to as much radiation as an hour in the sunshine), the radon appeared to be the explanation.

It wasn’t just quacks like Bailey who thought radiation was good for you. In an article in the American Journal of Clinical Medicine, a Dr. C. G. Davis claimed that “radioactivity prevents insanity, rouses noble emotions, retards old age, and creates a splendid youthful joyous life.” Other experts credited radiation with stimulating the body to throw off waste products.

Drink to your health

Water from natural hot springs was bottled and sold as a health tonic, but devotees claimed that the bottled stuff lost most of its healing properties after just a few days. This, too, appeared to be explained by the radon, which has a radioactive half-life of just 3.8 days. That means that half of the radon will decay into other substances in that time. At that rate, less then 1 percent of the radon would remain in the water after just one month.

If the radioactivity in spring water was what made it so beneficial, the thinking went, then water that had gone “flat” could be recharged by reirradiating it. There were numerous products on the market in the 1920s that enabled you do just that: You could buy a Zimmer Radium Emanator that, when dunked in a Revigator water crock, made from radioactive core.

All better now

Why stop with water? Companies sold radioactive hair tonic, face cream, toothpaste (for a glowing smile), blankets, soap, candy, chocolate bars, earplugs, hearing aids, laxatives, contraceptives, and countless other products that were credited with curing everything from pimples to high blood pressure to arthritis, gout, constipation, and chronic diarrhea.

In addition to Radithor radium water, William Bailey also sold radioactive flue and cough medicines, and an athletic supporter called a “radioendocrinator” that he claimed would cure impotence. Wearers were instructed to position the radium “under the scrotum as it should be. Wear at night. Radiate as directed…” Eben Byers took his doctor’s advice and began drinking Radithor. A lot of it. He found the water so “invigorating” that he continued drinking it long after his arm stopped hurting. Byer’s cure was more likely due simple passage of time than to any purported healing effects and radium, but he didn’t know that. In addition to downing as many as three bottles of Radithor a day for nearly three years, he sent cases of the stuff to associates and lady friends and urged them to drink it. He even instructed his stable boys to feed Radithor to his racehorses.

Too much of a “good” thing

Byers kept right on drinking Radithor into the early 1930s, when he began losing weight and suffering aches and pains all over his body. These symptoms were soon followed by blinding headaches and terrible pain in his jaw, but it wasn’t until his bones began breaking and his teeth started falling out that he realized he was suffering from something much more serious than “inflamed sinuses,” as his doctors had diagnosed.

Precisely what was wrong with him didn’t become clear until X-rays of his deteriorating jaw were sent to a radiologist in New York. The radiologist was familiar with the case of the “Radium Girls” – factory workers who had died after ingesting the radium in glow-in-the-dark paint while painting watch dials during World War I. The lesions on Byer’s jawbone were similar to the ones the Radium Girls had suffered. When the radiologist learned that Byers had consumed as many as 1,500 of Radithor since 1927, his diagnosis, like Byers’s fate, was sealed.

Radioactive Man

Had Radithor been made with radon gas dissolved in water, like the waters in natural hot springs, Byers probably would have escaped serious injury. But Radithor wasn’t made with radon, it was made with radium, a different radioactive element altogether. Radium’s half-life isn’t 3.8 days like radon’s – it’s 1,600 years. Even worse, because radium is chemically similar to calcium, instead of passing through the body in a day of two, which would have limited the amount of harm it caused, it accumulates in the bones, where the radiation if gives off destroys the surrounding bone marrow, blood cells, and other tissue. This was why Byer’s bone s were breaking and his teeth were falling out – they’d been destroyed by radiation and were no disintegrating. By the time he began to experience the first signs of radium poisoning, he had already consumed more than three times the lethal dose. He was doomed.

A Government Investigation

Even if the Food and Drug Administration had understood just how deadly radium was, in those days its powers to act were very limited. Radium was neither a food nor a drug, after all – it was a naturally occurring element, placing it outside the agency’s jurisdiction. The only government agency capable of acting was the Federal Trade Commission, which was empowered to protect consumers against misleading trade practices, including false advertising claims. Ironically, the FTC had used this power to take action against companies selling products that claimed to contain radioactive materials but didn’t.

By the time Byers fell ill, evidence of the dangers of radioactive products had begun to mount. The FTC opened an investigation into Radithor, which had been advertised as being “harmless in every respect.” Clearly it wasn’t and in 1931 a legal team was dispatched to Byer’s estate to record his testimony. By then he was too sick to appear in court. “A more gruesome experience in a more gorgeous setting would be hard to imaging,” attorney Robert H. Winn remembered:

We went to Southampton where Byers had a magnificent home. There we discovered him in a condition which beggars description. Young in years and mentally alert, he could hardly speak. His head was swathed in bandages. He had undergone two successful jaw operations and his whole upper jaw, excepting two front teeth, and most of his lower jaw had been removed. All the remaining bone tissue of his body was slowly disintegrating, and holes were actually forming in his skull.

The Fallout

Thanks in large part to Byer’s testimony, Radithor was pulled from the market in December 1931. Byers died three months later, at age 51. Any doubts that the radium killed him were resolved at the autopsy, when some of his teeth and a portion of his jawbone were set on a plate of unexposed photographic film: The radiation in the bone expose the file just as if it had been used in an X-ray machine. To prevent the radiation in Byer’s body from leaking out, he was buried in a coffin lined with lead.

No one knows how many people died from drinking Radithor. At least one female friend of Byers died from radium poisoning after he introduced her to the product. In all, dozens or possibly even hundreds of people may have been killed. Considering that William Bailey is estimated to have sold more than 400,000 bottles of Radithor over the years, it’s a wonder that more didn’t die. Many were probably saved by the price: Even when it was sold by the case, Radithor cost $1.25 a bottle (around $15 in today’s money). Few people would have been able to afford to consume as much as Byers had.

Lights Out

Byer’s death received a lot more press than those of the Radium Girls. (“The Radium Water Worked Fine Until His Jaw Came Off” read a Wall Street Journal headline.) Reason: Byers was a millionaire socialite; the Radium Girls were working-class nobodies employed by a paint factory. Very few people worked in such a place, so their story wasn’t as scary to readers as Byers’s, who’d died because he drank a health tonic sold to the public.

The scandal surrounding Byers’s death prompted the government to grant FDA much broader powers to regulate patent medicines and protect the public from other dangerous products. Another result: Today the sale of “radiopharmaceuticals” – radioactive materials used in medicine – is restricted to authorized members of the medical profession.

Caveat Emptor

If you collect antiques, you may know that some shops and dealers specialize in medical objects. From time to time an empty bottle of Radithor pops up, but think twice before you buy one – even though the bottles have likely been empty since their original purchasers consumed the product more than 70 years ago, the bottles themselves remain dangerously radioactive. Just like Eben Byers, still at rest in his lead-lined coffin in a cemetery in Pennsylvania, they will be radioactive for thousands of years to come.

 

SOURCE: Uncle John’s fully loaded 25th anniversary bathroom reader. (2012). Ashland, Or.: Bathroom Readers’ Press. p. 407 – 411

With ICH GCP E6 (R2) the emphasis is on Quality Management

For 19 years ICH GCP E6 has not changed. Now, nearly two decades after its initial release, change is coming. Perhaps the biggest difference is the focus and preeminence of Quality Management.

A modernized quality standard for clinical study processes is being espoused which is driving the adoption of Quality-by-Design and Quality Risk Management principles and methodologies by their full embrace throughout the guideline. Quality Management is expected to be risk-based, being applied to both the monitoring and auditing aspects of the clinical study process.

Going hand-in-hand with Quality Management is compliance. The draft addendum expands upon what is already written, by further stating that when there is significant non-compliance, it is the sponsors responsibility to perform a root cause analysis, implement corrective and preventive measures, and when needed, inform regulators. This facet of the Quality Management preeminence boosts the already existing quality-by-design and adaptive risk-based approach, with continuous improvement of the Quality Management processes themselves.

The changes being made to ICH GCP E6 (R1) reflect what is happening in the industry and are areas that have been highlighted by inspectors for several years. Some of these changes reflect guidance documents issued by regulatory authorities. These changes are expected to go into effect by November 2016. So mark your calendars.

For a consolidated list of the changes you can visit my blog, Ethics Nut, and scroll down to the post “Just the Additions – Consolidated Changes to ICH GCP E6 (R2).

For the full ICH GCP E6 (R2) you can access it here.

Review of Jennifer Hawkins Exploitation and Developing Countries

Jennifer Hawkins in her paper on exploitation and research ethics recognizes two principles of research which are being violated in many developing countries. She refers to the first principle as the principle of standard care, and the second principle the principle of clinical equipoise. Although these two principles seem to be logically inextricable, Hawkins notices that the two principles are not logically connected and that this can be seen when the two background assumptions usually associated with them are missing as can often be the case in developing countries.

The first principle requires research subjects to receive whatever the current standard of care is for the illness. If there is no treatment currently available then the use of placebos is allowed. The second principle the principle of clinical equipoise states that only under the condition that there is genuine disagreement within the medical community about which treatment is more beneficial for the subject are Randomized Control Trials (RCT) allowed to be used. Adhering to these rules provides researchers with the expectation that no one will be made worse off than prior to the research.

These two principles in the context of the developed world seem to be logically inseparable with the presence of two common background assumptions. The first assumption is that in the developed world there would never be any need to seek out new treatments which would be less effective than existing treatments. The second assumption is that in developed countries the treatments which are available are always the best existing treatments available and so there is no incentive to participate in research which may lead to someone getting inferior or dangerous untested treatment. When the assumptions which are present in the more developed countries are no longer applicable, such as the case in the less developed countries Hawkins thinks it is easier to see that satisfaction of one principle is neither necessary nor sufficient for satisfaction of the other.

The case in which standard of care is understood in terms of the standard which is locally available is an example under which one of the two principles can be satisfied without the other. To illustrate this, the example of a small imaginary tribe in Africa is useful. It is easy to envision such a tribe in a remote African area in which due to the remote location of the tribe the existing treatments are a fraction of the available options to those in more developed countries. Furthermore, because of economic restraints a vaccine with a slightly less effective than a full strength one may be of value because of the possibility of it being provided at a cheaper rate. Under these conditions both background assumptions are no longer present, and it can be seen how the first principle may be fulfilled without the second, supposing that the local remedies are wholly inadequate at fighting the disease when compared to western methods. In this scenario it would mean that the principle of standard care would be provided, the research subjects would be at least receiving the basic care normally provided and yet there would not be clinical equipoise. It would seem reasonable that within the medical community the majority would prefer the weaker version of the western vaccine than the local remedy. This shows that the two principles are logically independent of one another because the first principle would be fulfilled but not the second.

Thoughts on Peter Singer’s “Famine, Affluence, and Morality”

In the article Famine, Affluence, and Morality Singer argues for the position that the entire way we look at moral issues needs to be altered. The most crucial premise in Singers argument is this: “if it is in our power to prevent something bad from happening, without thereby sacrificing anything of comparable moral importance, we ought, morally, to do it.”[1]

I disagree with this premise. It does not incorporate enough factors in determining moral obligation. Merely, what is in our power, and without sacrificing anything of comparable moral importance are far too basic grounds to adequately determine what a moral obligation is. At least two other factors need to be considered those being, the relation between the person to that which needs help, and the distance between the two. Additionally it relies on an impossible calculation of what is of moral importance and presumes it is possible to compare two future paths in determining whether there is a moral obligation to help.

The relation that exists between the person, who is determining if they are morally obligated to help, and the person or object in danger, is a factor of importance. It is reasonable to place a higher moral obligation to someone who is closely tied to that which is in danger than a total stranger. For example, it makes more sense to say that a parent has a greater moral responsibility to save their child if it is drowning and they are capable of rescuing it, than a stranger standing next to them who has the same ability to save the child. Thus it is clear that the manner in which the two involved parties are interconnected must be of some importance.

Another factor which is important is the distance of which the person is from the bad occurrence. The further away the person is from the occurrence the greater the chance that someone closer can do the same task. The moral responsibility should thus fall upon them, or at least lessen the moral obligation of those further away from helping. For instance if someone requires help crossing a street and both a person standing fifty meters away and someone standing next to individual have it within their powers to help the person, it seems reasonable that the person closer has a greater obligation to help than the person further away. This does not show that distance completely negates moral obligations but it does make it reasonable to think that distance does to some extent play a factor in determining moral obligations. Moral obligations to provide aid rest upon the person closest to the incidence, not merely everyone who is capable of helping.

The final reason why I disagree with Singer’s premise is because it relies on an impossible calculation, namely the attempt to weigh what is of moral importance. I do not believe such a comparison is possible to the degree in which would be needed for this premise to be acceptable. Not only is it difficult to weigh what is and is not of moral importance, but it is even more difficult if not impossible to know if whether through certain actions something of possible greater moral importance will not be sacrificed. For instance assume a student wishes to go to a third world country for a year and volunteer to try and save some children’s lives. Although the student has done the calculations in their head and cannot see any downside to going away, they cannot know for a fact that they are not giving up something of possible greater moral importance had they chosen to stay. It could very easily be the case that while away the person misses the chance of meeting someone that they would have spent an amazing life with and could have with that person to help the children a few years later together.

[1] Singer, Peter. “Famine, Affluence, and Morality”. Philosophy and Public Affairs, Vol. 1, No.3 (Spring, 1972), 231

Science and the Swastika: The Deadly Experiment

If you are interested in the history of research ethics that goes beyond the typical one paragraph mention that normally accompanies the line about the Nuremburg Code this video is for you.

It discusses the experiments conducted in the concentration camps in a way I have not seen before and is a fascinating, humbling, and poignant reminder of how far we have come.

At just under 50 min this is a perfect video to watch on a lazy Sunday if you are interested in learning more about the origins of research ethics.

Link: https://www.youtube.com/watch?v=FZquBH0CH24

Disclosure in a Disaster Situation: Protecting Patient Privacy Rights with Public Safety

First and foremost it should be noted that the protection of a patient’s privacy is a right held by all patients regardless of ethnicity, religion, or other. It is a right which is to be respected in all situations, including that of a disaster. Patients always retain the right to determine through consent what information is disclosed, to who it is disclosed to, and for what purposes.

Consent to disclose information should be sought as early as possible either in writing or orally. This does not change in the event of a disaster but may prove more difficult. If consent is not provided the professional judgement of health care providers is to be used when disclosing information. Typically, in a disaster situation information on the patient’s whereabouts and current condition is shared at the first available opportunity to family members or friends involved in the care of the patient.

Despite the right of a patient to retain privacy and keep some information free from disclosure, the right to refuse disclosure is not always granted. A disaster situation may provide good reason for increased sharing of medical information.

If consent to disclose is provided, or if it is being done in the best interests of the patient, it is typically done only when a request for information is done under the condition that the name of the patient is given first. The patient has been referred to by name.

All of the above can be superseded if through disclosure of information the safety of public health is put into further jeopardy i.e. through disclosure the disaster spreads perhaps through alarmist irrational behaviour. Often however, when speaking of public safety in this context, it is an element which as a general principle is used to argue for increased information sharing so that hospitals can effectively coordinate their efforts.

In summary, basic health information can be disclosed in a disaster situation if consent is given, is in the best interests of the patient, or if there is a need for public health and safety. Information can likewise be withheld if disclosure would enhance the disaster, consent is not given, or if it is not in the best interests of the patient.

Just the Additions – Consolidated Changes to ICH GCP E6(R2)

Hello,

If you haven’t already heard there are changes coming to everyone’s favourite…the ICH GCP.

For a consolidated look at just the changes you can take a look at them all in one document I’ve created.

Here is the link to download: https://andrewmilroy.files.wordpress.com/2015/11/consolidated-changes-to-ich-e6r2-by-andrew-milroy-14-nov-2015.pdf

Enjoy!

Andrew

Towards Trans-cultural Process Based Ethics: Silencing critics of clinical trials in developing countries

PROPOSITION

As things now stand, Ethical Pluralism and the avoidance of a modern ethical imperialism of sorts, allows for exploitation or at a minimum the appearance of exploitation to persist, and has been taken off the table concerning acceptable strategies in dealing with developing countries, making its acceptability something of a moot point. If taken stringently, in practice it would undue years of work towards universalising ethical codes for research involving human subjects. Moral universalism has intrinsic and inescapable problems tied to imperialism of values and cultural norms. It offers a totalitarian stance on how things ought to be and all but ignores important differences between cultures. Procedural pluralism an approach not discussed in depth herein is on the right track but is only just beginning to come to some structured definition. Although it is arguably currently allowing for exploitation to persist with large variances in the capacity of local institutions to properly assess clinical trials and a remaining difficulty with what to take as “standard of care”, these can be overcome with capacity building clauses and reviews from developing world taken as universal decisions.

The position being proposed is for a new push towards a trans-cultural process based ethics. Trans-cultural process based ethics hopes to take the procedural necessity from ethical pluralism but aims to shape it into a more stringent universal form with standards. Questions then diverge from whether ethical committees merely exist, to whether they meet universalized standards of what is required to function unbiased and in a manner which could silence the criticism. With a new look at the role capacity plays in claims of exploitation, criticism of pharmaceutical companies which say that the absence or malfunction in many instances of local ethics committees is what is making developing countries so attractive to large pharmaceutical companies may be silenced.

ARE CLINICAL TRIALS EXPLOITATIVE?

Large pharmaceutical companies are increasingly moving into international markets to develop therapies, making clinical trials in the developing world a core component of their business models. Looking at the United States, one third of their trials are being conducted outside the country, many in countries which are still developing. Pushing this move is the desire to help local health care concerns, lower costs, and expedite the time taken to conduct these trials. Reasons for these trials are there contribution to the development of national economies and health care systems, along with enabling higher standards of quality. They offer global access to academic expertise and patient populations.

In countries which have healthcare budgets of less than ten dollars per person per year, clinical research can benefit entire communities. Backed with large funding budgets a country can benefit greatly by maintaining an environment ideal for clinical research through which entire healthcare systems can be developed and capacity built. For pharmaceutical companies developing nations offer pools of patients not otherwise found in the developed world, allowing for research on drugs to take place which would otherwise be impossible.

With the increase of clinical trials in the developing world there has been increased concern after several well known instances, one of which involving HIV trials in Africa, have fed the fires of criticism over these trials. The criticism largely revolves around the double standard of care which can be found in developing countries that allow for these trials to exist and increase in popularity because of savings associated with cost and time.

Declarations such as that of the Declaration of Helsinki, adopted virtually universally in the world, show a trend which aims at making ethical considerations more explicit when determining ethical acceptability of humans in research. However, with these declarations providing minimum recommendations to what is acceptable there are radical differences between how they are interpreted in practice. High standards which are espoused in these declarations critics say, are not being espoused in practice and questions such as “Is it ethically acceptable to confine subjects in the control arm to treatments which are considered substandard in the sponsoring country of the study?” persist in delivering heated debate in the medical community.

Serious questions about which standard of care to use in a control arm of a study remain and are compounded with questions of the ability of ethics committees in developing countries to function properly. On one side we can find proponents of a position which would push for ethical pluralism, allowing for local ethics committees and standards to trump positions and therapies found in developed countries. The other side can be summarized within a moral universalism ideology. They push for universal standards and weighting of principles, uphold opinions coming from ethical committees and review boards from developed nations, and demand standard of care requirements to be defined as that of best globally rather than locally. Depending on which of the two camps one finds themselves in changes the entire appearance of the debate.

As with all debates that have been around for some time, there is a third camp which takes a sort of middle ground. They can be said to fall within procedural pluralism which can be taken to mean that the declarations which are been agreed upon are universal in some sense, although they are goals rather than principles and which in their attainment, can be ethically allowed to differ from differing cultural contexts. They place tremendous importance to local ethics committees and their autonomy to make decisions for the communities for which they serve. It is perhaps within this arm of the debate that progress can be made at turning what appear to be exploitative practices into clear examples of ethical research.

This proposal looks at the current disparity between international and local standards, what it means to the existing debate, implicitly shows a need for a new approach for approval of international clinical trials, and states what that approach could be.

EXPLOITATION (Universalism vs. Pluralism)

Due to less stringent regulatory constraints and income disparities, trials can be carried out quicker and cheaper in a developing country rather than developed. A core criticism to international clinical trials is that the level of income found in developing countries means that people are often more willing to participate. They are, it is argued, more vulnerable than participants in wealthier nations.

Problems for ethical research in a developing country include 1) a health system which may function inadequately, leaving patients to join trials mistakenly in search of treatment, 2) troubles offering well informed participants able to make informed consent due to poverty, illiteracy, a hierarchical doctor-patient relationship, and lack of access to treatment, and 3) a lack of training needed to conduct trials according to ethical standards. These problems pose serious questions to the ethical nature of any trial being conducted in such a setting.

There is such a discrepancy between clinical environments that many have even ventured to ask if fair participant selection, a core tenant of ethical research, is even possible. This is attributed to the fact that participants could very well be coerced through economic reasons or because they cannot receive treatment otherwise. In instances found in India where physicians are paid large sums to recruit participants, it is difficult to ensure that procedures meant to provide consent are genuine and legitimate. Again those who argue for an ethical pluralism stance for administrating clinical trials, sway opponents by noting that clinical research in these communities is necessary and that it meets their standards, that is the local standards, for what is ethically permissible. Similarly, with informed consent difficulties surrounding its acquisition are usually excused with claims that the guidance of universal declarations do not take into account local circumstances where Western consent procedures may conflict with cultural norms and notions of autonomy.

Despite the shortcomings of local capacity to adhere to international standards, ethical pluralist side with a position that would have local ethics committees and their outputs trump that of developed nations on the position that their autonomy and standards should be recognized. Moral Universalists however, claim that it is precisely the low standards at the local level which allow for exploitation to occur. If universal standards were used, such exploitation would not exist. The disagreement on whether to use universal standards or a pluralistic stance on what is to be acceptable is precisely what has led to criticisms of exploitation.

STANDARD OF CARE Developed vs. Developing

The question of whether exploitation exists in clinical trials which are conducted in developing countries is unresolved. This is largely dependent on how existing universal principles found in declarations such as the Declaration of Helsinki are interpreted at the local level. For example, withholding in a control arm a therapy known to be effective albeit in an intensive and expensive form for the common local therapy is construed as ethical relativism. Moral Universalists would argue that you cannot withhold the better Western treatment or therapy. What should be taken as the “standard of care” whether local or global is of crucial importance and is far from being resolved.

Standard of care, or the best standard of care is meant to protect vulnerable participants from being unjustly harmed through deprivation of standard medical treatment while in an experiment. In essence no patient in a trial funded by the United States should be denied the ‘standard of care’ available in the United States. Problems arise though when one examines the reaction to changes made to the Declaration of Helsinki which stated it is a worldwide best standard which should be used in a control arm. The reaction was a rejection by every national and international committee that reviewed it. This rejection however, leaves the benchmark for control arms arguably far too low. Moral Universalists would claim that we cannot waiver on a global standard of care which ought to be provided while ethical pluralists would claim a more context based answer involving the local treatments which are commonly provided can be sufficient. The claim that all research subjects are entitled to minimum guarantees that are transnational and non-negotiable is widely accepted although realisation of these entitlements often falls far short in practice. There is another double standard at play though which complicates the debate and that is of the quality and capacity of ethics committees in developing countries to participate at international standards.

There have been incidences of ethics committees in wealthy countries approving studies that would not be allowed in their own country to be conducted in poor countries. Critics, Moral Universalists, claim that different standards of research ethics are being applied, one for developed countries, the other for the developing ones. Cultural differences are being used to validate clinical trials with the primary responsibility for assessing proposals left with the relevant ethical review committees in the developing countries. This is problematic because it is often more difficult to conduct scientifically sound research in countries where basic healthcare is not widely available and research ethics committees are underdeveloped or absent.

A major concern is the ability of regulatory agencies and ethics committees to function properly, without their functioning, declarations and the principles found within cannot be upheld as intended. With wide disparities in terms of economic, social standing, and their health care systems, the fear is that the lack of capacity in developing countries jeopardizes the rights of research patients by bringing in trials which should not be approved. One study for example showed that only 56% of the 670 researchers surveyed in developing countries stated that their research had been reviewed by a local institution review board or health ministry. In another study 90% of published clinical trials conducted in China in 2004 did not report ethical review of protocol.

Those who would continue clinical trials in countries where a lack of proper oversight is abundantly clear, highlight the need for a different balance to be met between risks and benefits where there are differences between resources and health conditions. This leads again to their falling under an ethical pluralist stance which shows that from their side, a study may be acceptable in one country but not in another because of differences in wealth or burdens of disease. The very fact of a discrepancy of acceptability does not warrant a claim of exploitation it is said. Those who continue to defend such trials associate a great deal with the process requirements of a trial. From the fact that the trials are being supported by local governments and approved by ethics committee, it should be seen as a trial which is not exploiting the local population but rather one which builds the local healthcare system and capacity of participating healthcare practitioners.

International conventions have little practical guidance for when local ethics committees show a lack of capacity. More worrisome is that although guidelines advise investigators to submit proposals for ethical review in both the funding and receiving country, they are silent on the question of primacy concerning differing opinions on acceptability and other matters. If we look to the Council for International Organizations of Medical Sciences than the problem can be said to be exacerbated when it states “the host country’s ethics committee has a ‘special responsibility’ on matters of detail of a trail, such as acceptability of plans to obtain informed consent, while committees in the sponsoring body need only to be satisfied that the trial conforms broadly to the ethical standards prevailing in their own country.” This gives an almost trumping status to ethical review committees which may have major shortcomings concerning expertise. Only a handful of African nations currently have the capacity for growing international requirements. They along with non-African nations tend to have under-developed mechanisms and procedures. The countries which have the most vulnerable populations to clinical trials have the least developed systems to review such research.

As questions such as whether the ‘best proven diagnostic and therapeutic method’ refers to international standards or should we take local resources into consideration, and whether healthcare needs and budgets justify ethical standards in developed countries to differ from the developing, the debate on whether these trials are exploitative will continue. Although there is already a recognized need for universal guidelines and regulatory requirements to minimize conflicting reports, these guidelines can often led to two very different answers. Agreements must be made further on the weighting of principles and exactly how the more detailed aspects of clinical trials in the local context can universally be handled. An additional ‘layer’ of guidance between the universal and contextual is clearly needed. Similarly harmonisation is needed between existing research ethics guidelines.

While there has been considerable work done on what makes clinical research ethical, with the development of principles and benchmarks to guide ethics committees, there has been considerably less research done on overcoming differences in views of exploitative research or claims made thereof. As claims of exploitation can severely damage the reputation of a pharmaceutical company which is conducting clinical trials in developing countries in what is considered by them ethical and non-exploitative there must be a method developed to deal with resolving claims of exploitation. We should go further than consensus building on what is deemed ethical. We should aim to develop a method whereby existing principles are untangled from one another and whereby through, an as of yet developed structure for analysis, clinical trials which involve multiple cultures may realize their benefits without facing what some times appear as inherent criticisms of exploitation.

REFERENCES

David M. Studdert and Troyen A. Brennan “Clinical trials in developing countries: scientific and ethical issues”. The Medical Journal of Australia 1998 Vol 169 pg.545-548

Ezekiel J. Emanuel et al. “What Makes Clinical Research in Developing Countries Ethical? The Benchmarks of Ethical Research”. JID March 1, 2004 Vol 189 pg. 930-937

Francis P. Crawley “Developing Clinical Trials in Africa: Building the Scientific, Regulatory and Ethical Frameworks”. Journal for Clinical Studies Nov. 2008 pg.16-17

Greg Koski et al. “Research Involving Human Subjects in Developing Countries”. The New England Journal of Medicine July 12 2001 Vol 345;2 pg. 136-138

Michael J. Selgelid “Module Four: Standards of Care and Clinical Trials”. Developing World Bioethics 2005 Vol. 5;1 pg. 55-72

National Bioethics Advisory Commission “Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries”. Report and Recommendations of the National Bioethics Advisory Commission April 2001 pg. 1-12

P.K. Julka “Clinical Trials in India: Dilemmas for Developing Countries”. Issues in Clinical Research April 2007 pg. 69-71

Yousefi- Nooraie et al. “Registration of Clinical Trials: How Developing Countries Could Prepare for the Upcoming Storm”. Archives of Iranian Medicine July 2008 Vol 11;4 pg. 361-363

Seth W. Glickman et al. “Ethical and Scientific Implications of Globalization of Clinical Research”. The New England Journal of Medicine Feb. 19 2009 Vol 306;8 pg. 816-823

Soren Holm “Moral pluralism”. The ethical aspects of biomedical research in developing countries, Proceedings of the Round Table Debate Oct. 1 2002 pg. 9-10

Wemos Foundation “Call for Ethical Clinical Trials in Developing Countries”. Fair Drugs Feb. 2009 pg. 1-7

Wemos Foundation “Do European registration authorities ascertain whether clinical trials in developing countires have been conducted in an ethical manner?” Fair Drugs June 2007 pg. 1-8

Online Training Tools for Clinical Research Coordinators

by Andrew Milroy – HRPP and CQA Manager (Merita CQA)

Online training is becoming increasingly popular in nearly every field allowing for training of professionals from the comfort of their own office or home. In the field of clinical research there are several well known online training tools such as the TCPS 2 CORE Tutorial offered by the Interagency Advisory Panel on Research Ethics, and the Collaborative Institutional Training Initiative’s (CITI) ICH GCP training.

Listed below are six online training tools, including those mentioned above, that offer clinical research coordinators a means by which they can upgrade their credentials, refresh their knowledge, or just remain current with the latest developments and ideas.

The TCPS 2 Tutorial – Course on Research Ethics (CORE)

CORE provides an applied approach to the guidance provided in TCPS 2. This self-paced course is a media-rich learning experience that features interactive exercises and multi-disciplinary examples. CORE consists of eight modules ranging from Core Principles to REB Review. It is designed primarily for the use of researchers and REB members – though anyone may take this course and print their own certificate of completion.

http://www.pre.ethics.gc.ca/eng/education/tutorial-didacticiel/

Collaborative Institutional Training Initiative’s (CITI) Program’s Good Clinical Practice (GCP)

GCP courses are suitable for research teams involved in clinical trials of drugs, biologics, and devices.

GCP for Clinical Trials with Investigational Drugs and Medical Devices (U.S. FDA focus) is suitable for individuals proposing to conduct clinical trials of drugs and devices primarily in the U.S. and/or who would prefer a more U.S. FDA-centric curriculum.

GCP for Clinical Trials with Investigational Drugs and Biologics (ICH Focus) is suitable for individuals involved in clinical trials on drugs and biologics when the research may be international or where the individuals would prefer a more ICH-focused curriculum. This ICH E6 GCP Investigator Site Training meets the Minimum Criteria for ICH GCP Investigator Site Personnel Training identified by TransCelerate BioPharma as necessary to enable mutual recognition of GCP training among trial sponsors.

GCP for Clinical Trials with Investigational Medical Devices is most appropriate for organizations or individuals who desire a more international-focused GCP curriculum or a more device-focused program.

https://www.citiprogram.org/

 

Ethical and Regulatory Aspects of Clinical Research

This course is offered by the NIH to anyone interested or involved in the ethics of clinical research with human subjects. Participants represent multiple disciplines including research teams, IRB members, physicians, psychologists, nurses, social workers, administrative staff, students, and others.

http://www.bioethics.nih.gov/courses/index.shtml#ethical

Introduction to the Principles and Practice of Clinical Research (IPPCR)

The Introduction to the Principles and Practice of Clinical Research (IPPCR) is offered by NIH and is a course to train participants on how to effectively conduct clinical research. The course focuses on the spectrum of clinical research and the research process by highlighting epidemiologic methods, study design, protocol preparation, patient monitoring, quality assurance, and Food and Drug Administration (FDA) issues. Other areas covered include data management and ethical issues, including protection of human subjects, building a budget, plus many special topics.

http://clinicalcenter.nih.gov/training/training/ippcr.html

Training and Resources in Research Ethics Evaluation (TRREE)

TRREE is headed by a consortium of interested persons from Northern and Southern countries. It aims to provide basic training, while building capacities, on the ethics of health research involving humans so that research meets highest standards of ethics and promotes the welfare of participants. TRREE achieves this goal primarily by developing a training programme with local collaborators. In its initial stages TRREE focused primarily, but not exclusively, on the needs of African countries.

TRREE provides free-of-charge access to:

e-Learning: a distance learning program and certification on research ethics evaluation

e-Resources: a participatory web-site with international, regional and national regulatory and policy resources

The e-learning programme is based on internationally recognized ethical principles and regulations. It integrates local issues and perspectives from low-and middle-income countries, most notably from African countries, that are relevant to all those who must ensure the protection of research participants and who promote highest ethical standards.

http://elearning.trree.org/

The Lab: Avoiding Research Misconduct

In “The Lab: Avoiding Research Misconduct,” you become the lead characters in an interactive movie and make decisions about integrity in research that can have long-term consequences. The simulation addresses Responsible Conduct of Research topics such as avoiding research misconduct, mentorship responsibilities, handling of data, responsible authorship, and questionable research practices.

http://ori.hhs.gov/thelab

This list is not exhaustive and if you are aware of other available online training tools please feel free to contact me so that I can review and consider utilizing them for training purposes.

I can be reached at amilroy@meritacqa.com if you have any questions or would like to share additional online training tools.

References:

TCPS 2 Tutorial :: The Interagency Advisory Panel on Research Ethics (PRE). (n.d.). Retrieved December 3, 2014, from http://www.pre.ethics.gc.ca/eng/education/tutorial-didacticiel/

Collaborative Institutional Training Initiatives. (n.d.). Retrieved December 3, 2014, from https://www.citiprogram.org/

Courses, Lectures, & Training. (n.d.). Retrieved December 3, 2014, from http://www.bioethics.nih.gov/courses/index.shtml#ethical

NIH Clinical Center: IPPCR. (n.d.). Retrieved December 3, 2014, from http://clinicalcenter.nih.gov/training/training/ippcr.html

TRAINING AND RESOURCES IN RESEARCH ETHICS EVALUATION. (n.d.). Retrieved December 3, 2014, from http://elearning.trree.org/

The Lab. (n.d.). Retrieved December 3, 2014, from http://ori.hhs.gov/thelab

Code Brown – Some Trivia for your Long Weekend

Was reading “Uncle John’s Funniest Ever Bathroom Reader” and came across a piece worth sharing. Here it is:

Code Brown

Actual abbreviations and terms used in the ER by doctors and nurses who – by necessity – have a morbid sense of humor

TMB: Too Many Birthdays (suffering from old age)

FORD: Found On Road Dead

House Red: Blood

TRO: Time Ran Out

Frequent Flyer: Someone who is regularly taken to hospital in an ambulance, even though they aren’t sick (because it’s something to do)

Code Zero: Another name for a “Frequent Flyer.” The real radio codes range from Code 1 (not serious) to Code 4 (emergency)

Code Yellow: A patient who has wet the bed

Code Brown: (You can guess this one yourself)

FOOSH: Fell Onto Outstreched Hand (a broken wrist)

T&T Sign: Tatoos-and-teeth. (Strange but true: Patients with a lot of tatoos and missing teeth are more likely to survive major injuries.)

DFO: Done Fell Out (of bed)

MGM Syndrome: A “patient” who is faking illness and putting on a really good show

WNL: Will Not Listen

SYB: Save Your Breath, as in, “SYB, he WNL”

Insurance Pain: An inordinate amount of neck pain following a minor auto collision with a wealthy driver

ALP: Acute Lead Poisoning – a gunshot wound

ALP (A/C): Acute Lead Poisoning (Air Conditioning) – multiple gunshot wounds

Flower Sign: Lots of flowers at a patient’s bedside (may indicate the patient is a good candidate for early discharge, since they have people who can care for them)

ART: Assuming Room Temperature (deceased)

Bagged and Tagged: A corpse ready for the morgue (it’s in a body bag and has a toe tag)

AMF Yo Yo: Adios, Motherf@#*!, You’re On Your Own