Business Ethics - Opioids Crisis

BMGT 496 - Week 4 Citations

(Evans, 2017)

(Hadzima Jr., 2006)

(Lexie, 2020)

(National Research Council (US) Committee to Study the Human Health Effects of Subtherapeutic Antibiotic Use in Animal Feeds, 1980)

(Pearl, 2017)

(Phillips & Cohen, 2021)

(Seres, 2017)

(Silverman, 2016)

(Stratton, Palombi, Blue, & Schneiderhan, 2018)

(Thielking, 2015)

(Weigmann, 2015)

Bibliography Evans, J. (2017, December). The War on Opioids: An Ethical Perspective. Caring for the Ages,

18(12), 14. doi:https://doi.org/10.1016/j.carage.2017.11.012

Hadzima Jr., J. G. (2006, December). The Importance of Patents: It Pays to Know Patent Rules. Boston Business Journal, 1-2. Retrieved April 6, 2021, from http://web.mit.edu/e- club/hadzima/pdf/the-importance-of-patents.pdf

Lexie. (2020, November 3). 5 famous whistleblowers who risked everything. Retrieved April 6, 2021, from ExpressVPN: https://www.expressvpn.com/blog/5-american-famous- whistleblowers/

National Research Council (US) Committee to Study the Human Health Effects of Subtherapeutic Antibiotic Use in Animal Feeds. (1980). Appendix K. In The Effects on Human Health of Subtherapeutic Use (pp. 317-376). Washington, DC: National Academies Press. Retrieved April 6, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK216502/#ddd00236

Pearl, R. (2017, January 19). Why Patent Protection In The Drug Industry Is Out Of Control. Retrieved April 6, 2021, from Forbes: https://www.forbes.com/sites/robertpearl/2017/01/19/why-patent-protection-in-the- drug-industry-is-out-of-control/?sh=2741ef9f78ca

Phillips & Cohen. (2021, March 19). Our Successful Whistleblower Cases. Retrieved April 6, 2021, from Phillips & Cohen: https://www.phillipsandcohen.com/successful-cases/

Seres, D. (2017, March 30). The Danger Of Loosely Regulated Supplements. Retrieved April 6, 2021, from American Council on Science and Health: https://www.acsh.org/news/2017/03/30/danger-loosely-regulated-supplements-11070

Silverman, E. (2016, November 6). Supreme Court lets pay-to-delay ruling against pharma stand. Retrieved April 6, 2021, from STAT News: https://www.statnews.com/pharmalot/2016/11/07/supreme-court-pay-delay-glaxo-teva/

Stratton, T. P., Palombi, L., Blue, H., & Schneiderhan, M. E. (2018, August 1). Ethical dimensions of the prescription opioid abuse crisis. American Journal of Health-System Pharmacy, 75(15), 1145-1150. doi:https://doi.org/10.2146/ajhp170704

Thielking, M. (2015, October 14). Unregulated supplements send thousands to hospital each year. Retrieved April 6, 2021, from STAT News: https://www.statnews.com/2015/10/14/unregulated-supplements-send-thousands-to- hospital-each-year/

Weigmann, K. (2015, May). The ethics of global clinical trials: In developing countries, participation in clinical trials is sometimes the only way to access medical treatment. What should be done to avoid exploitation of disadvantaged populations? EMBO Reports, 16(5), 566-570. doi:https://doi.org/10.15252/embr.201540398

14 CARING FOR THE AGES D E C E M B E R 2 0 1 7

scribe them. There is a war on opioids in this coun-try — and on the people who pre-

We are in the midst of a public health crisis of addiction that has already taken the lives of many people and is straining our limited resources for fi rst responders and emergency care.

B ecause many deaths occur from the misuse of prescription-only drugs — and there have been many highly publicized instances of unscrupulous prescribers running “pill mills” — many people nat- urally assume that the medical profession is the source of the problem. The power and privilege of prescribing medications are limited to a relative few, and with this great power comes great responsi- bility; popular resentment is only to be expected whenever power is perceived to be abused. As a result, fear and distrust of the medical profession have increased, along with the intense effort, now well underway, to discourage physicians from prescribing opioids.

“W e all have strength enough to endure the misfortune of others.” —François de La Rochefoucauld

H owever, the opioid crisis involves many deeper causes. Socioeconomic fac- tors have contributed to the profound hopelessness and despair that many peo- ple live with every day. And prescription opioids continue to be widely available from illicit sources, as is heroin, which often is combined with fentanyl.

I am not making ex cuses on behalf of the medical profession — quite the contrary. I want to emphasize even more broadly the moral and ethical responsi- bility of health care providers, the chang- ing ethos of health care, and the grave risks to all the caring professions and our professional values as we navigate this storm.

History of Opioid Use The histor y of opioid use is the his- tory of medicine. The fi rst recorded use of opium for medical purposes dates back at least 5,000 years. The Ebers papyrus from 1550 B.C. described the medicinal preparation and use of opium in Egypt. Hippocrates discussed the important medicinal uses of opium in 460 B.C. Opium has been continu- ously modifi ed for medical use since then. The use of opium in the form of laudanum was described by Paracelsus in 1527. Morphine was commercially

manufactured by Merck and Company in 1827, and its use in injectable form was developed in 1840 in Scotland.

The dev elopment of surgery and all its related subspecialties would have been impossible without opioids. Although many other analgesics have been discov- ered or developed since aspirin, none are as potent or effective as opioids for the treatment of severe pain. But the history of medicine and the history of opium are also the history of addiction.

Just Say No “Just Say No” was the mantra of the war on (illicit) drugs begun in the early days of the Reagan administration some 35 years ago. The same refrain is being heard again today by prescribers of opioids, along with a reminder of Hippocrates’ admonition to “fi rst do no harm” (primum non nocere). Some believe that doing no harm supersedes any obligation to do good (benefi cence). But the obligation to do good is far more fundamental: it is the guiding principle of all caring professions and has formed the basis of every civil soci- ety in history.

It is a mistake, however, to assume that most practitioners even want to prescribe opioids. Most prescribers are generally (and increasingly) afraid to. And most report inadequate training in pain man- agement, fear of enabling addiction, and fear of getting in trouble. Prescribing opioids is more than an inconvenience. We are required to view our patients with suspicion — they could be lying to us or drug seeking. We must check up on them in a database. But if we aren’t allowed to trust them, why should any patient trust us? Our job, our obliga- tion, and our calling is to love and care for others, not to judge them. And we resent it, more than anything, when they judge us.

I ndeed, many physicians now are heed- ing the call to just say no. An increas- ing number of practitioners, including board-certifi ed pain specialists, are fl atly refusing to prescribe opioids for any rea- son. Even within our professions the sug- gestion is increasingly being made that we are weak because we can’t stand pain.

B ut think about what it means to our profession, and to our society, if as pre- scribers we all just say no.

What if we just say no to cancer patients, to patients with acute fractures or major surgery, to dying people, and to people whose pain is so bad they wish they could die? It means, at a minimum, we are indifferent to human suffering. It means that we keep all the power to prescribe to ourselves yet avoid any of

the responsibilities that go with it. It means that ours are no longer the car- ing professions — because we no longer care. We become technicians following algorithms, and we can soon be replaced by computers that are better at it and no less caring.

T o refuse to accept responsibility for another’s comfort and well-being is to repudiate all our professional values, which thus requires a renunciation of all the associated privileges.

Medical care is inherently dangerous. Our obligation isn’t to avoid practicing medicine, it’s to make it less danger- ous. Hippocrates’ admonition to fi rst do no harm was not an admonition to never treat, and it did not supersede his instructions on the use of opioids and other inherently dangerous medicines. We are, however, obligated to know the harm — to weigh the benefi ts and risks, and to guide decision making through authentic, informed consent, based on real knowledge of the risks and benefi ts, rather than on collective ritual practice. And we are obligated to monitor and guide the patient, and to accept personal responsibility for the welfare of another whole person, not just our favorite dis- ease or body part.

S trategies to try to limit our responsi- bility only limit our worth as profession- als and as human beings.

Accepting Responsibility The history of medicine is the history of medicines. Indeed, the word physi- cian literally means “drug giver.” Despite our collective history of more than 5,000 years of medicines, however, we do a lousy job of prescribing them. It is estimated that more than 250,000 Americans die every year as a result of taking (mostly nonopioid) medicines exactly as prescribed. That number has likely increased since the introduction of Medicare Part D drug coverage to seniors, the age group that is at highest risk for adverse drug effects. The one- size-fi ts-all approach to drug prescribing for adults in the United States further increases the risk to older patients.

The benefi ts of medicines are exag- gerated and the risks minimized in the minds of almost every prescriber (and most patients). There is widespread, willful ignorance among prescribers about the risks, benefi ts, mechanisms of action, and elimination of almost every medicine prescribed. This is a deep cultural fl aw in American health care. A student of surgery would be expected to know all the steps of a surgical proce- dure backward and forward along with the potential complications before ever

being allowed to proceed under close supervision. But that same individual need only know what symptom or prob- lem a medicine is ‘for’ in order to pre- scribe it. Nor is that student’s teacher expected to know more.

We also do a terrible job of under- standing age-related changes in anatomy and physiology, as well as drug–drug and drug–disease interactions to prevent serious problems caused by medicines. Medical specialties do not even take responsibility for disseminating infor- mation about new drugs to their prac- titioners — instead, they leave it to the pharmaceutical sales force. So whatever condemnation we receive for prescribing medications is well deserved, even if at times somewhat misguided.

We should be experts on all the drugs we prescribe. It should be a source of professional pride. If these are the tools of our trade, then we must master them. Prescribers should be leading the national dialogue on safe and appropriate prescribing of opioids, not hanging our heads or running the other way. It is our moral obligation, and maintaining the integrity of our professions requires that we lead the call for monitoring and safe- guarding the prescription drug supply in this country, ensuring timely, appropri- ate access to opioids for the patients who need them, those for whom adequate substitute treatments do not exist. We should be leading the charge for univer- sal access to addiction prevention and recovery, along with access to expertise in effective pain management and con- trol. And we should actively police our own profession for those who abuse the privilege of prescribing by doing so inap- propriately, and those who abuse the privilege of practicing medicine by turn- ing a blind eye to human suffering.

The challenges to safe and effectiv e pain management, including appropri- ate opioid prescribing, are many and are made worse by increasingly fragmented care and communication across settings and across practitioners even for a single episode of illness. But none of these chal- lenges are as great — or as great a threat to our professions and our professional values — as the prospect of becoming indifferent to human suffering and to our awesome responsibility and privilege to relieve that suffering.

Dr. Evans is a full-time long-term care physician in Charlottesville, VA, and medical director of two skilled nurs- ing facilities. A past Society president, he serves on the Caring for the Ages Editorial Advisory Board.

MEDICAL ETHICS Jonathan Evans, MD, MPH, CMD

The War on Opioids: An Ethical Perspective

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5 famous whistleblowers who risked everything

L E X I E Last updated: November 3, 2020

D I G I TA L F R E E D O M 4 mins

“See something, say something” is a safety and awareness campaign running across multiple

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cities in the United States.

If you see misconduct, criminal activity or just something suspicious, you are expected to alert the authorities.

But what if it’s the authorities that are doing something wrong, by abusing their power or acting suspiciously? Ideally, an institution should have internal complaints mechanisms, an Ombudsperson or an external anti-corruption agency.

Members of the United States Intelligence Community, however, find it difficult to raise concerns internally and those that do are often ignored.

Additionally, whistleblower protection often does not apply (e.g., to contractors), and must only be reported to Congress.

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What happens to those who do manage to blow the whistle? Of the famous examples below, one is in jail, one has done jail time, one is awaiting trial, one is in exile, and the other is on the run.

1. Edward Snowden In 2013, ‘Ed’ left his job with a U.S. defense contractor for Hong Kong, taking with him 10,000 documents detailing the U.S. surveillance apparatus.

Snowden handed this trove to journalists who for years continued to release the information in various dossiers covering surveillance, espionage, hacking, and civil rights violations.

Edward Snowden was given asylum in Ecuador but, due to the U.S. canceling his passport en route, became stranded at Sheremetyevo airport

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in Moscow. He was granted temporary asylum in Russia, where he continues to live until today.

2. Daniel Ellsberg Daniel Ellsberg released the Pentagon Papers in 1971 and detailed the continuous lies of the Lyndon B. Johnson administration regarding the war in Vietnam.

The documents were photocopies Ellsberg was able to make during his work at the RAND Corporation and, at first, he tried to convince Senator Fulbright to release the papers to the Senate (because a Senator could not be prosecuted for something they say on the floor).

When that failed, Ellsberg sent the documents to the New York Times, which quickly received a

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court order forbidding them to publish or report on its contents.

Ellsberg, still on the run from the FBI, mailed the documents to other newspapers, including the Washington Post, which finally published the stories.

Ellsberg’s trial in 1973 revealed that the government had illegally wiretapped Ellsberg and even broke into his psychiatrist’s office to find discrediting information. The case was thrown out by the court.

The Pentagon Papers were only fully released and made available to the public in 2011.

3. Chelsea Manning

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Chelsea Manning was an Intelligence Analyst with the U.S. Army stationed in Iraq. She had access to classified databases containing videos, diplomatic cables, and war logs from Afghanistan and Iraq— which she released to Wikileaks.

Some of the content detailed American war crimes in Iraq, including the murder of Reuters journalists and those who aided the wounded.

Chelsea Manning told an online acquaintance about her actions, which resulted in her capture. Chelsea faced charges that could have resulted in the death penalty but received a sentence of 35 years in maximum security prison.

In 2017, the sentence was reduced to seven years by President Obama, and she was released the same year.

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4. Reality Winner A U.S. military contractor employed Reality Winner, where she was able to obtain a document about Russia’s interference in the 2016 election, which she made available to the publication The Intercept.

Authorities caught Winner because of metadata found on the documentswhich revealed the printer she used. She was sentenced to five years and three months in jail, the longest such sentence by a federal court for releasing information to the media.

There is hope Winner might be pardoned by President Trump, who voiced his support for Winner in a Tweet.

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5. Shadow Brokers The Shadow Brokers are a hacking group (and whistleblowers) active since 2010. They alert the public about security vulnerabilities created and exploited by the NSA.

The leader of the Shadow Brokers is Harold T. Martin III, a contractor with the same company Snowden worked with before he blew the whistle.

Some speculate that Shadow Brokers is the work of Russian counter-intelligence, acting with the aim of undermining the NSA in its global operations.

Harold T. Martin III is currently under arrest and awaiting trial.

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Bonus: Paul Revere a whistleblower? Paul Revere was an American Revolutionary who literally blew a whistle in 1775, alerting American revolutionaries about the arrival of British colonial militia.

While not commonly referred to as a whistleblower, the British forces did at the time rule over the colonies. Their acts of power were lawful, while the revolution was illegal.

Doing what’s right is not always doing what’s legal, and the many women and men who do what’s right in the face of jail time or even the death are heroes.

Anonymity is an essential tool for staying safe as a whistleblower. Be careful, but do get help, from reputable journalists and lawyers and

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technologists when alerting the world about the crimes conducted by authority.

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NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

National Research Council (US) Committee to Study the Human Health Effects of Subtherapeutic Antibiotic Use in Animal Feeds. The Effects on Human Health of Subtherapeutic Use of Antimicrobials in Animal Feeds. Washington (DC): National Academies Press (US); 1980.

Appendix K Antibiotics In Animal Feeds

Committee on Animal Health and the Committee on Animal Nutrition

Board on Agriculture and Renewable Resources National Research Council

Executive Summary The food-producing animal and poultry industries have undergone a dramatic change that began around 1950. What was an extensive industry became extremely intensive: units increased in animal concentration, both physically and numerically. Utilization of the beneficial responses of feed-additive antibiotics in improved growth and feed efficiency developed concurrently with the intensification of the animal industry. It has been proposed that feed-additive antibiotic usage was an integral part of this revolution in animal-production technology. It is estimated, at present, that 40 percent of the antibiotics produced are used for feed additives. Estimates allocate 0.5 million kg to the cattle industry, 1.0 million kg to poultry, 1.4 million kg to swine, and 0.4 million kg to other animals such as companion animals.

The animal producer can obtain antibiotics in the form of balanced supplements and premixes that are processed and sold by the feed-manufacturing industry. The producer also has access to and can purchase antibiotic products from farm and veterinary supply centers. Administration of antibiotics in the drinking water is becoming increasingly important in both poultry and swine production.

Feedlot systems for beef cattle and sheep would not change if low-level antibiotic feedings were not permitted, but it is likely that disease problems and therapeutic use of antibiotics would increase.

The discontinuance of low-level (5 to 10 g/ton) usage of penicillin and tetracyclines would have little effect on the poultry industry. However, the elimination of higher levels (100 to 200 g/ton) would make it very difficult to control bacterial disease in young chickens and turkeys. If all tetracyclines and penicillin were banned as feed additives for poultry, the effective alternative antibiotics and sulfa drugs would likely maintain present production and efficiency standards. However, the problem of selective pressure for some multiple antibiotic resistance mediated by plasmids may still persist with alternative antimicrobials.

If only tetracyclines and penicillin were banned as feed-additive antibiotics for swine, there would be little if any effect on swine productivity or efficiency. There are other promising antibacterial agents that could serve the industry well.

If subtherapeutic use of feed additive antibiotics is banned, future changes in disease control will include preventing exposure to infectious agents, treatment of disease after an outbreak has occurred, and control of infectious disease by immunological means. Preventing exposure to infectious agents will be extremely difficult and will result in a slowing down of animal production. Post-outbreak treatment has had variable effectiveness, but would certainly be less effective than the present use of subtherapeutic levels of antibiotics. The control of infectious disease by immunological means would be an ideal way to safeguard against subclinical infection. However, thus far there has been limited success in protecting animals against bacterial pathogens that affect the intestinal and respiratory tracts.

Antibiotics have been effective in improving the rate and efficiency of gain in swine, cattle, and poultry. The responses in poultry and swine are generally greater in younger animals than in those reaching the end of the growing-finishing period. There is some evidence that the improved farrowing rate of swine is associated with the use of antibiotics. Responses in cattle have not been as great as those in swine and poultry. Improvement in rate of gain and feed efficiency in cattle has averaged about 5 percent. Evidence indicates that the effectiveness of antibiotics has not decreased over time.

Antibiotics in feed have also been used in animal production in Europe since 1953. The British have monitored microbial resistance to antibiotics and have conducted some basic and applied research concerning this aspect. Although the use of antibiotics in the United Kingdom has been restricted as a result of the Report of the Joint Committee on the Use of

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Antibiotics in Animal Husbandary and Veterinary Medicine (referred to in this report as the Swann Report; Swarm et al. 1969), the total tonnage used in animal production in 1975 was at an all-time high. Although the amount used in animals was only about 15 percent of the total usage, the ratio of the human population to the livestock population receiving antibiotics is substantially higher than in the United States.

Ingestion of antibiotics results in the development of resistance in bacteria such as in the E. coli and Salmonella species. The resistance appears to be related to usage patterns. British research has shown that resistance persists longer following long-term use, compared to short-term use. There is strong evidence that development of resistant strains of bacteria in humans is closely related to antibiotics used in humans. No concrete evidence has been reported in the United Kingdom showing that antibiotic resistance has decreased since the Swann Report, or that antibiotic use has decreased.

The wise use of antibiotics is not a substitute for, but a complement to, good sanitation and husbandry practices. Extensive use of low-level antibiotics in feeds has brought about concern for potential harmful effects due to development of resistant strains of organisms in host animals that might compromise animal as well as human health. Drug resistance in bacteria was observed soon after the introduction of antibiotics. Antibiotics have been used extensively in animal feeds for nearly 30 years. Questions and discussions concerned with the potential human health hazards from subtherapeutic antibiotic feeding to animals have been aired for nearly 30 years. Yet, it is difficult to cite human health problems that can be attributed specifically to meat animals fed antibiotics or that can be associated with contact with animals fed low levels of antibiotics. There have been incidents of salmonellosis in humans involving antibiotic resistant strains of animal origin but there is no evidence of any relation to low-level antibiotic feeding.

Surveys of the use of drugs for therapeutic purposes indicate that antibacterial agents account for almost 50 percent of drugs used by practicing veterinarians. In vitro testing has sometimes been questioned in that infections associated with organisms that seem to be resistant in vitro are quite responsive to antibacterial therapy in vivo in clinical use.

Scattered reports, published and unpublished, attribute failure in drug therapy to low-level antibiotic feeding. Others claim continued effectiveness of drugs previously fed for long periods at subtherapeutic levels. Carefully controlled studies exploring possible relationships between antibiotic feeding and subsequent drug effectiveness are needed.

Critical experimental studies on the effect of low-level antibiotic feeding on animal therapy and human health are de finitely needed. It is proposed that studies be conducted in the following areas:

Does the Feeding of Tetracycline and Penicillin Compromise Animal Therapy?—This research should be done with swine, poultry, and cattle. In swine and poultry, conditions should be closely controlled. In cattle it would seem essential that research be conducted in commercial-type feedlots.

The Relationship of Antibiotic Feeding to Human Health— Although these studies are very complex and time- consuming, it is important that some effort be started in this direction. The incidence of disease-resistant organisms could be determined in humans in industries in which the workers have close contact with animals and animal products and with people who work in industries that have no contact with animals or animal products. Also the incidence of disease and the effectiveness of therapy should be studied. Some information might be obtained by surveys of existing information.

Mechanisms of Action of Antibiotics in Growth Promotion— Current evidence strongly suggests that the growth- promoting effect from low-level feeding of antibacterial compounds is not solely related to disease prevention. Knowledge of the mechanisms involved is a vital missing link. If known, the study of other means of eliciting a similar response would become feasible. Thus, such new knowledge would offer the potential for eliminating some or all of the current reasons for using feeding levels of antibacterial drugs.

Chapter 1. Introduction The use of subtherapeutic levels of penicillin and the tetracyclines in animal feeds has raised the question of the effects of such practices on human health. The Food and Drug Administration (FDA) has proposed a ban on certain antibiotics at subtherapeutic levels in feed because of the potential for compromising the health of humans. A large segment of the regulated industry, including farmers and ranchers, has contended that in nearly 30 years of use, antibiotics at

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subtherapeutic levels in animals have not compromised human or animal health or influenced the therapy of human disease.

The FDA has contracted with the Assembly of Life Sciences, National Academy of Sciences, for a review and evaluation of human health effects of antibiotics in animal feeds. The Committee to Study Human Health Effects of Subtherapeutic Antibiotic Use in Animal Feeds has been appointed to:

study the human health effects of subtherapeutic use of penicillin and tetracyclines (chlortetracycline and oxytetracycline) in animal feeds;

review and analyze published and unpublished epidemiological and other data as necessary to assess the human health consequences of the subtherapeutic use of penicillin and tetracyclines in animal feeds; and

assess the scientific feasibility of additional epidemiological studies, and, if needed, to make recommendations about the kind of research necessary, its estimated cost and time requirements, and possible mechanisms to be used to conduct such studies.

Under the terms of the contract, subtherapeutic levels are defined as use of the agent at levels of 200 g/ton or less, and/or use of the agent for 2 weeks or longer. Animal feeds include milk replacers, medicated blocks, and liquid feeds.

The Committee has requested the Board on Agriculture and Renewable Resources (BARR) to prepare a critical review/position paper on certain aspects of the problem. The following list of questions to be answered was submitted to the BARR (the Chapter numbers after each question refer to the chapter in this report that discusses the question):

How effective are antibiotics—especially penicillin and tetracycline—in animal feeds? (Chapter 3)

Would animal husbandry methods change if antibiotics were eliminated, or if penicillin and tetracyclines were removed? (Chapter 2)

Does animal disease decrease as a result of use of antibiotics and would there be an increase in therapeutic use of antibiotics if subtherapeutic use was discontinued? (Chapter 2)

What do the data from European countries show with respect to animal health and nutrition where antibiotics have been restricted? Has the restriction of subtherapeutic use led to increased therapeutic use, thus cancelling the benefits of restriction? (Chapter 4)

Is it likely that there would be a black market? (Chapter 2)

How much therapeutic use is there and has it caused resistance problems? What is the evidence that therapeutic use of penicillin and tetracyclines contributes to resistance and possible health effects? (Chapter 6)

What epidemiological studies exist that would be valuable for the committee to consider? Are there epidemiological studies that should be carried out? (Chapter 6)

What amounts of penicillin and tetracyclines are used subtherapeutically? (Chapter 2)

What amounts of penicillin and tetracyclines are used therapeutically? (Chapter 6)

How are animal feeds prepared and how are the antibiotics used in animal feeds mixed and used by farmers or feedlot operators? (Chapter 2)

How are antibiotics for therapeutic use in animals regulated? Do veterinarians have guidelines or antibiotic audits? (Chapter 6)

Has therapeutic efficacy been compromised by the use of subtherapeutic levels of antibiotics in animal feeds? Are resistant infections more prevalent in animals? (Chapters 5, 6)

Critically review the documentation for increase in resistance, pathogenicity, and increase in numbers of pathogens after use of subtherapeutic antibiotics. (Chapters 5, 6)

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BARR asked its Committees on Animal Nutrition and Animal Health to set up a panel of their members and outside consultants to address these questions. The Panel met on June 11 and July 2 to 3, 1979, and prepared the statement that follows that addresses the 13 questions.

The panel is indebted to Enriqueta C. Bond and Roy Widdus, of the Division of Medical Sciences, for providing published research documents on the subject, and to Philip Ross and Selma P. Baron for their advice and guidance in the preparation of the report.

Chapter 2. Subtherapeutic Use of Antibiotics

Animal Management

Swine

Pig production in the United States is more diverse geographically than broiler, turkey, and feedlot cattle production. About 90 percent of the nation's pork supply is produced in the 12 north central states plus Georgia, Kentucky, North Carolina, and Texas. The number of pigs slaughtered in the United States has varied from about 73 to 95 million head per year and yielded about 25 to 36 kg (carcass basis) annual per capita consumption for the U.S. citizen during the last 15 years.

The swine industry has changed from an enterprise that historically employed pasture to one that predominantly employs confinement buildings and concrete lots. The swine industry differs from the broiler industry, however, since nearly all the production is by private producers rather than by industrial entities. An appreciation of the change to intensive swine production is evident in Table 2.1. There has been a dramatic decrease in the number of farms which produce pigs, both nationwide and in Iowa, the largest producing state. The total production trend has changed little, except year-to-year responses to feed cost and pig selling price relationships.

Evidence of the continuing intensification since the 1974 census in the swine industry is provided by survey information obtained in 1975 and 1978 from large producers in the United States (Stemme et al. 1978, 1979). The number of producers that market 5,000 head or more and those producing from 2,500 to 4,999 head has increased during the 3-year period (Table 2.2). The annual production of this group of producers would account for more than 20 percent of the total U.S. production. Over 70 percent of the producers in this group have confinement housing facilities. Their worst problem in their farrowing facilities was reported to be E. coli scours.

A new organizational form in pork production, the subsidiary sow-farrowing firm or sow-farrowing cooperative, has come into existence since 1970. These firms are organized generally by a group of producers as subchapter S corporations or cooperatives.

The purpose of the organization and production unit is to produce feeder pigs (40 1bs) for the members or shareholders who do not want to farrow pigs, but do want to finish them (40 1bs to 220 1bs) on their farms (Hepp 1977, Paulsen and Rahm 1979). In Iowa 63 such firms were identified that began operation since 1974. The breeding herd size of those firms in the second year of production averaged 537 sows with an annual production capability of more than 8,000 feeder pigs each (Paulsen and Rahm 1979).

With intensification the disease problems have also changed. Historically, hog cholera, swine erysipelas, tuberculosis and brucellosis were the disease problems most troublesome. These have largely disappeared due to eradication programs. With concentration and confinement production the enteric diseases and respiratory diseases are the most prevalent problems reported.

As a group, both the large producers and the organized sow-farrowing firms employ an early weaning management system whereby the nursing pigs are weaned at 3 to 4 weeks of age. In 1976 an average investment of $1,176 per sow in the unit was reported (Paulsen and Rahm 1979). Because of the high fixed costs, the management places a high priority on total production. With early weaning the sow can be re-bred within a few days after her pigs are weaned and thereby increase the number of pigs produced per sow per year. Historically nursing pigs were weaned at 8 to 10 weeks of age and the sows were not re-bred until their farrowing date fit expected mild weather and/or the other activities associated with the farm enterprise, such as corn planting or harvesting. In the process of early weaning, natural protection from enteric disease problems in young pigs has been diminished (IgA immune globulins in sow's milk).

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It is interesting to note that the introduction and use of feed-additive antibiotics has been concurrent with change in production technology in the swine industry. It is likely that the use, of antimicrobial agents has facilitated the development of the concentrated operations.

Poultry

As part of the effort to produce poultry meat and eggs as economically as possible, it is common practice in the United States to maintain broilers, turkeys, and laying hens in large flocks in one location. From 10,000 to 20,000 broilers are typically raised in one house and some operations have as many as a million laying hens in one location. With such a concentration of birds it is essential to have disease control programs that will prevent disastrous losses to the poultry industry. Drugs, including the antibiotics, have played a major role in maintaining the health of poultry flocks since the 1950's.

The management procedures used in today's poultry production have made it possible to provide poultry meat and eggs for consumers very economically. In fact, until very recently the prices of broilers and eggs were similar to those 25 years ago despite a decrease in the value of the dollar through inflation. It is unlikely that future changes in management will result in any reduction in the concentration of poultry. Changes will probably involve upgrading of physical facilities for maintaining the birds, including environmentally controlled housing and the adoption of more automated equipment in the feeding and management of the birds.

Cattle And Sheep

In 1962 feedlots with a capacity of 1,000 head or more accounted for 40 percent of fed cattle marketings, while in 1978 lots of this size marketed 68 percent of the fed cattle (USDA 1979a). Due to the economics of feeding, increases in concentrations can be expected, but at a slower rate. As concentrations of feedlot cattle have increased, there has been increasing need for improved management and management systems.

Penicillin is not used in cattle feeding in the United States. However, the continuous low-level use of other antibiotics in cattle feeding is regional. In the more arid areas of the Southwest, there is no response to antibiotics as growth promotants, and therefore, they are not continuously fed. This lack of response appears to be related to climate. In the remainder of the feeding areas, low-level continuous feeding of antibiotics is routine. An estimated 50 to 60 percent of feedlot cattle are fed low-level antibiotics during the feeding period and a total of 40 percent of the total beef supply has been fed low-level antibiotics (USDA 1979b).

Amount Used And Feed Preparation

Swine

Feed requirement for swine is estimated at about 4.40 kg of feed per kilogram of liveweight sold at market (Van Arsdall 1978). In 1978 about 88 million head were slaughtered in the United States with an estimated average liveweight of 250 1bs. So in total, about 44 billion kg of feed were consumed by swine. The FDA (U.S. DHEW/FDA 1978) from the U.S. International Trade Commission (1974) data estimated the production of feed-additive antibiotics at 3,350,000 kg. About 10,000 feed mills manufacture or mix feeds containing drugs and they supplied about 12 million tons of feed to the swine industry. Several types of products are sold to farmers. Most of the feed-manufacturer tonnage is sold as supplements (protein, minerals, vitamins, and feed additives) to be further mixed or diluted with grain for feeding as a complete balanced diet by the swine producer.

A more concentrated form manufactured is a premix (vitamins, minerals, and feed additives). The premix is further mixed by an intermediate or secondary feed mill or mixed by the producer using grain and generally soybean meal as a protein source. Most pig starter diets used by the producers are purchased from a feed manufacturer as a complete feed. The purchase of complete mixed diets for the other stages of production is not as prevalent. The market structure of the feed industry is presented in Figure 2.1. Antibiotic usage by the feed industry is controlled by periodic inspections and sampling by representatives of the FDA and state feed-control inspectors. Such things as drug inventory control, approved levels of incorporation, product claims, and assay of finished product are monitored.

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2.

The consumption of feed-additive antibiotics per market pig is estimated in Table 2.3. It is estimated that in 1978, the 88 million pigs marketed consumed 1,408,000 kg of antibiotics or about 40 percent of the feed-additive antibiotics produced.

Poultry

Very little use is made of penicillin and the tetracyclines for low-level feeding (5 to 10 g/ton) for stimulating growth in poultry production. A major reason for this is that these antibiotics are not approved by the FDA for use in combination with monensin (''Coban,'' an anticoccidial drug). Monensin is used in about 85 percent of the broiler feed prepared in this country. Only the antibiotics lincomycin, bacitracin, and the bambermycins can be used at low levels in combination with this anticoccidial drug (Anonymous 1979c).

Very little penicillin is used in poultry production either for subtherapeutic or therapeutic purposes. Some penicillin is used in the diluent for Marek's disease vaccine, which is injected into day-old chicks. It is also used as a treatment for erysipelas in turkeys at a level of 100 g/ton plus a level injected to provide approximately 5 mg/kg body weight. Apparently little or no penicillin is used for treatment of diseases in chickens.

The tetracycline drugs are used quite extensively for treatment of diseases and for improving suboptimal performance of birds. Frequently, tetracycline (200 g/ton) or a combination of oxytetracycline (50 to 100 g/ton) and neomycin (35 to 140 g/ton) is used in the starter feeds for both turkeys and broilers. These are used in the first 0.23 kg of feed for each bird. In the case of broilers, the anticoccidial drug is removed since the combinations are not permitted by FDA regulations. The antibiotic drugs during this period of time are used to control several bacterial diseases and to get the birds off to a good start. Considerable amounts of tetracyclines are also used in laying hen diets at various times. From 50 to 100 g/ton are used for a 2-to-3-week period to improve shell quality and egg production in laying hens, particularly during the latter part of the laying cycle.

Most of the feed mixed for poultry production in the United States is made by large integrated companies and in large feed mills where careful control of the inclusion of the drugs and other feed ingredients is maintained on inventories. The feed manufacturers, in using drugs in poultry rations, must follow regulations of the FDA and be inspected periodically by this agency and state feed control officials.

A point that should be emphasized is that poultry producers do not indiscriminately use antibiotics in poultry feeds. Poultry operations only use antibiotics when their cost will be more than covered by the improved performance of the birds.

Ruminants

Based on approved claims, tetracyclines serve four purposes in cattle rations: (1) control of liver abscesses; (2) control of respiratory disease related to shipping fever; (3) control of foot rot; and (4) improved gains and feed efficiency (Anonymous 1979c). Cattle finishing diets contain high levels of grain and the incidence of liver abscesses increases as the level of grain feeding increases. Low-level feeding of the tetracyclines may reduce the incidence of liver abscesses by as much as 50 percent (Foster and Woods 1970, Woods 1970, Davis 1978). Daily gains in steers with liver abscesses may be depressed by 5 to 10 percent. No doubt a portion of the increased gain noted because of low-level feeding of the tetracyclines is due to the reduction of liver abscesses. On the basis of 1970 cattle and feed prices, Foster and Woods (1970) estimated a $9.30 loss for each animal with an abscessed liver. This value considered both feed cost and liver loss due to condemnation.

Subtherapeutic use of tetracyclines in cattle feeding may be divided into two categories (Woods 1970, Anonymous 1979c).

Incoming cattle may be fed 250 to 1,000 rag/day for a 7- to 28-day period after receipt for control of shipping fever. The highest feeding level would be equivalent to 200 g antibiotic per ton of feed. For incoming cattle, administration of antibiotics via water may also be used. During the feeding period, levels of 250 to 1,000 mg/day may be fed for short periods during outbreaks of respiratory problems. After recovery from shipping fever, the level is reduced to 70 to 80 mg/day for the remainder of the feeding period in areas where continuous feeding of low-level antibiotics is practiced.

For growth promotion and improvement of feed efficiency, the recommended levels of feeding are 70 to 80 mg/day (Anonymous 1979c). This may be included in the total feed or the daily supplement in areas where the ration is fed as grain, roughage, and supplement. The combination of chlortetracycline and sulfamethazine has been shown to be effective for control of the shipping-fever complex in cattle (Woods 1970).

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The tetracyclines have been used primarily for disease treatment with lambs, although continuous feeding at 20 to 50 g per ton of feed has been shown to be beneficial for growth and aid in reduction of enterotoxemia. However, effective vaccines are available for enterotoxemia. Improvement of growth of suckling lambs occurs when the tetracyclines are included in the creep ration at 20 to 50 g per ton of feed (Beeson 1978).

The tetracyclines up to levels of 100 g per ton in milk replacer and starters for baby calves are effective in growth promotion and control of bacterial scours (Warner 1972).

Effects of Restrictions

Swine

The removal of antibiotics as feed additives, while continuing their therapeutic or prescription usage, would not necessarily reduce the total quantity used.

If antibiotics were eliminated as feed additives, it is questionable whether production in confinement swine operations could be maintained at an intensive level. It is likely that weaning age would be increased. Inventory would be reduced, more labor and time would be required to thoroughly clean and disinfect between groups of pigs, and the breeding herd efficiency would be reduced to conform to calendarized farrowings. In the long run, because of the increased cost of operating confinement units, a reversion to extensive or pasture production could take place. The seasonal nature of extensive production would mean large month to month variability in marketings reminiscent of historical patterns and would be disruptive for today's packing industry.

Poultry

The discontinuance of the use of penicillin in poultry feeds would have little effect, since this antibiotic is not used extensively at the present time. The only major problem would be in the treatment of erysipelas in turkeys since this antibiotic seems to be particularly effective against this disease. The complete removal of the tetracyclines, however, would have a much greater impact on the industry. Restriction of the use of these at low levels (5 to 10 g/ton) for growth stimulation would have little effect since they are not used now to any extent for this purpose. The elimination of the use of higher levels of tetracyclines, how ever, would create problems in the control of bacterial diseases in young chickens and turkeys and in maintaining optimum performance of laying hens. What undoubtedly would happen with the restriction of use of tetracyclines in feeds is a much greater use of these anti biotics in the water. This would lead to increased cost of medication and probably would result in no general reduction in the use of total quantities of tetracyclines in poultry production.

Ruminants

Unless the tetracyclines are completely restricted for use as a subtherapeutic low-level feeding, the resident veterinarian might prescribe them for low-level feeding to prevent certain disease problems.

Feedlot systems for beef cattle and sheep would not change if low-level feedings were not permitted. Disease problems and carcass condemnations would increase, and therapeutic use of antibiotics would increase.

Economic Effects of A Ban on the Use of Antibiotics

Potential economic effects of a ban on antibiotic feed additives for 1973 livestock output, price, and cost conditions were examined by Gilliam and Martin (1975). They considered two hypothetical ways in which producers might react to such a ban: (1) by feeding additional numbers of beef cattle, veal calves, and hogs to achieve pre-ban output levels; and (2) by feeding the same number of animals on the same schedule, with the result of reduced output.

In situation (1), increased costs of production would be $801.7 million, assuming no change in mortality and no change in the cost of feeder cattle and pigs. If the costs were borne by consumers, annual per capita red meat costs would increase $3.85.

In situation (2), the annual expenditures for red meat would increase $2,134.5 million annually or $10.26 per capita.

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If mortality increased in either situation, costs would be estimated to increase $0.36 to $1.25 per capita for each 1-percent increase in death rates.

A U.S. Department of Agriculture study (USDA 1978) considered the effects of a total ban on feed-additive antibiotics for each species of food-producing animals, assuming moderate drug efficiency and high drug efficiency. They cónsidered the impact on total farm income and changes in consumer food costs during the first year of a total ban, and then the adjustments that would occur in 5 years. Their conclusions are summarized in Table 2.4. It is interesting to note that total farm income is projected to rise the first year. This is because of the inelastic relationships between price and supply for meat products.

Headley (1978) reported the results of an econometric analysis on the meat-animal industry as a result of banning different drug combinations. The consumer and national costs are presented in Table 2.5. The estimates of the economic impact to the industry and consumers appear to be realistic.

Future Changes In Antibiotic Use

As research in the control of diseases and the maintenance of optimum health continues, the use of antibiotics in the future will undoubtedly change. Producers will use the most economical means of preventing diseases to attain the lowest cost of production per unit of meat or eggs. If new vaccines, alternative drugs, and total eradication programs become more effective and/or more economical than the use of tetracyclines, these methods will replace the use of tetracyclines.

The concentrated raising of cattle, swine, and poultry has brought about new problems in control of infectious disease. Conditions have changed: the number of farms raising livestock has decreased 80 percent since 1940, and yet the number of animal units has doubled. The control of infectious disease has been responsible for the success of these concentrated enterprises. Such control is particularly important for young susceptible animals during the rapid growth phase. The main methods of controlling infectious disease are:

Preventing Exposure to Infectious Agents—Attempts to raise swine under specific pathogen-free conditions in strict isolation have been tried, but found to be expensive and impractical. Cattle can be raised successfully and disease controlled through range-type rearing. However, this system would result in reducing total beef production by approximately 50 percent as feedlot production would be lost. Isolation of dairy animals has been partially successful where calves are fed ample levels of colostrum and herds are confined. Some success has been achieved at raising poultry in isolation, but this is not a practical procedure by itself.

Subtherapeutic Use of Antibiotics—This approach has made possible the disease control and production gains known today. However, it has created an antibiotic-resistant bacteria problem that may affect the use of these drugs in both man and animals.

Treatment of Disease After Outbreak has Occurred—This technique is difficult and impractical especially in young stock because losses occur rapidly and morbidity and mortality during the growing period have major unrecoverable effects on production.

Control of Infectious Disease by Immunological Means— The main concerns in controlling infectious diseases in cattle, swine, and poultry are immunizing young animals and protecting the portals of entry, such as the respiratory and intestinal tracts. Under the present conditions of concentrated production, the natural protection afforded by maternal antibodies should be utilized by allowing the young to suckle for as long as possible.

There has been little success thus far in protecting animals against bacterial respiratory and intestinal pathogens. Certainly strides are being made in developing immunogens for certain coil-form organisms, but solid long-term protection against pathogens of the respiratory and intestinal tracts may be difficult to produce. The immunological approach to disease control will not replace the use of antibiotics in the near future.

Alternatives

Resistance characteristics similar to those from tetracyclines and penicillin evolve when most other approved feed-additive antibiotics for swine are fed (Fagerberg and Quarles 1979). Certain sulfa drugs may be eliminated as feed additives because of residue problems, and carbadox and furazolidone are possible carcinogens. o Bacitracin and Flavomycin

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(bambermycins) are not viable alternative feed additives, since they lack efficacy for the young pig (Hays 1978). Virginiamycin is the only approved feed-additive antibiotic that would then remain that would be efficacious for the young pig and growing-finishing pigs. Similar microbial defense mechanisms are likely to emerge against virginiamycin or against new antibiotics developed specifically for animal use.

In some situations, antibiotics other than the tetracyclines or penicillin could be used for the treatment of diseases in poultry. With few exceptions penicillin could be replaced by other antibiotics presently available. Elimination of tetracyclines would create more of a problem because these appear to be the most economical and effective for certain purposes in poultry production.

A detailed description of the approved subtherapeutic use and levels of the tetracyclines for cattle is given in the Feed Additive Compendium (Anonymous 1979c). At the present time, besides the tetracyclines, only three antibiotics (tylosin, bacitracin, and erythromycin) are available for subtherapeutic use in feedlot cattle. The only approved claim for tylosin is as an aid in reducing liver abscesses. Tylosin costs three times as much as the tetracyclines. While there is an approved claim for erythromycin for growth promotion and feed efficiency, it has not been used in the field. Very little field information has been developed for the use of bacitracin in cattle feeds. There is no approved substitute for chlortetracycline-sulfamethazine combination used for control of the shipping-fever complex.

If feed-additive drugs were available therapeutically via prescription, there probably would be little or no reduction in usage in swine, poultry, and ruminants.

If feed additives were not available through approved channels, violations by segments of the industry would be likely. Examples would include the use of chloramphenicol, dimetridazole, and high levels of copper sulfate.

Alternatives to feed-additive drug usage, discussed in more detail below, might include the following: (a) environmental and management changes, (b) selection for genetic resistance, (c) development of vaccines, (d) adoption of minimal disease programs, and (e) development of new feed additives that do not promote bacterial resistance relevant to human and animal health.

Environmental and Management Changes

Reducing the production intensity of facilities would reduce the enteric problems commonly encountered in farrowing and baby pig facilities, and would reduce respiratory problems in cattle feedlots. A time lapse between groups would allow adequate time for more thorough cleaning and sanitation of the facilities. As new facilities are constructed for swine, knowledgeable producers are building modified isolation rooms with reduced capacity to allow the opportunity for better sanitation between farrowings. In the case of broilers the use of cages would also allow for improved sanitation. A recent innovation has been the use of small wire-penned enclosures for young pigs which reduces the chance of contamination from one pig to another.

Progressive swine producers are becoming more appreciative of herd isolation to reduce disease problems. Many of the more intense units are applying artificial insemination as a means of introducing new blood lines into the herds. By raising their own boars and gilts for breeding herd replacements, producers avoid the risk of introducing new animals, possibly bearing new diseases, into the herds.

Selection For Genetic Resistance In Natural Immunity

Although information on this topic is limited, there are indications that older animals are more resistant to respiratory problems than younger ones. Usually, older, lactating sows confer an immunity to their offspring not present in pigs from young sows. Also some strains or breeds of animals may be more susceptible to respiratory and enteric problems.

Development of Vaccines

The need for disease control by antibiotics could be reduced by vaccinating animals for certain disease conditions, commonly the most troublesome in production. A bacterin was recently developed to control atrophic rhinitis in swine, and was successfully demonstrated in the field. Research is in progress on similar approaches for control of mycoplasma and E. coli organisms and the agent for porcine pleuropneumonia.

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Adaptation of Minimal Disease Programs

Swine herds free of respiratory problems can be maintained in that condition for some reasonable period of time. This state can be attained by hysterectomizing pregnant sows and raising the young pigs in isolation in the first generation. Subsequent generations are obtained naturally. The largest problem has been the accidental reintroduction of respiratory diseases. For this approach to be successful over long periods of time, complete isolation from man, pets, birds, and rodents is essential, which would be impractical.

Development of New Antibiotics

There are new experimental antibiotics effective for swine that are not being used in human medicine. Whether they have all the desirable attributes by present-day standards is not known. The goal of research should be the development of such compounds that avoid the characteristics that are thought to pose health hazards of men and animals as recognized by today's standards.

Chapter 3. Efficacy Of Antibiotics In Animal Feeds

Swine

Several compilations of the average weight gain and feed efficiency improvements from feed-additive antibiotic additions to swine diets have been reported since the discovery of anti biotic growth stimulation (see Table 3.1). These reports represent mainly research or experiment-station trials, and it has been suggested that the improved performance observed in research facilities because of better sanitation and disease control is a conservative estimate of the response of animals fed in commercial production facilities. The percentage of responses in the young animal are great, but decrease as the animal nears market weight (Hays 1978). This is explained by the performance of the control animals and their increasing daily gain as they mature.

Hays (1978) compared present-day efficacy of antibiotics to their past effectiveness. The liveweight gain response of young pigs fed tetracyclines during the 1967 to 1977 period was greater than during the 1950 to 1956 period. Feed efficiency response was not as great, but the initial weights of the experimental pigs used in the 1967 to 1977 comparison was considerably greater (7 vs. 11 kg liveweight). The percentage of responses during the growing and finishing phases of production were not as great, but the liveweight gains of the growing pigs fed tetracyclines were essentially the same, while the rate of gain of the controls in the 1967 to 1977 group improved more than 11 percent for growing pigs and 3 percent for growing-finishing pigs compared to groups of animals used in the 1950 to 1956 comparison groups.

Beneficial effects of antibiotics on farrowing rates of sows have been summarized (Speer 1979c) in Table 3.2. In most cases the antibiotic or chemotherapeutic was fed at the rate of 1.0 g/sow/day for a short time before and after mating (about 20 days). Sows fed the control diets averaged 68.4 percent and sows fed the control diets plus drug averaged 77.4 percent farrowing rate.

An increase in the number of pigs farrowed by sows fed antibiotics before mating has been reported in a few experiments, but there is not enough evidence on this production trait to demonstrate that it has had a real effect.

Poultry

It is generally conceded that management, housing, disease elimination, disease control, isolation, and genetic improvement is far more sophisticated in the poultry industry than any of the other industries. Poultry production facilities can be completely vacated between groups of birds, the facilities thoroughly cleaned, and then the whole production unit filled with birds of the same age and at the same time. Yet, improvements in production traits as a result of antibiotic administration are clearly evident from the summary data presented in Table 3.3. The only production criterion that was not improved was percent hatchability for turkey breeders. A comparison of the responses to antibiotics reported in the literature since 1970 compared to the period 1950 to 1977 was examined by Hays (1978). It can be concluded that the antibiotics continue to be as effective as they were originally.

Cattle And Sheep

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Feedlot cattle rate of gain and feed efficiency responses to antibiotics are both improved about 5 percent (Table 3.4). The tetracyclines have been the most widely used antibiotics in the beef cattle industry. (Recently monensin has been approved for use for improved feed efficiency in feedlot cattle. General use by the industry has been rapid. Only tylosin in combination with monensin has been approved for use at this time.) The response seems to be greater on high-roughage rations than low-roughage rations. A marked reduction in the incidence of liver abscesses in feedlot cattle fed antibiotics, particularly the tetracyclines or tylosin, is economically significant both from improved performance in the feedlot and increased carcass value. Responses in calves, both dairy and veal, are greater than with older cattle (Table 3.5). Feed- additive antibiotics have no recognized beneficial effects for the milking dairy cow.

Like other farm species, the young lamb responds to low levels of antibiotics (10 to 25 g per ton of diet). The response of western feeder lambs seems to be more variable. The tetracycline antibiotics are more commonly used in feeder lamb diets. Low levels of these antibiotics reduce the incidence of enterotoxemia in feedlot lambs.

Chapter 4. Restrictions on Antibiotics in Europe

Background

Most of the activities concerning restriction of antibiotic use were initiated in the United Kingdom following the Swann Report (1969). Action in other European countries followed that of the United Kingdom. The British were among the first in Europe to use antibiotics extensively as growth promotants.

In 1947 a Penicillin Act was passed by the British Parliament prohibiting the sale of antibiotics except for medical and veterinary use (Braude 1978). In 1953 the Therapeutic Substances Act was passed following research in the United States and the United Kingdom showing substantial economic advantages from including penicillin or chlortetracycline in the diets of young animals, and advice from the Medical Research Council that no adverse effects were observed in humans eating meat from antibiotic-fed animals. The regulation allowed inclusion of penicillin or chlortetracycline at a maximum of 100 g/ton to diets of growing pigs and poultry. Later, oxytetracycline was approved. Use of antibiotics in ruminant feeds was not approved.

In 1956 workers convened by the Agricultural Research Council concluded that the only potential danger from feeding antibiotics was the possible establishment of resistant strains of pathogenic microorganisms. In 1960 a Joint Committee was appointed by the Agricultural and Medical Research Councils, under the chairmanship of Lord Netherthorpe. In the first report this committee recognized that continued exposure of a bacterial population to an antibiotic leads to a progressive reduction in sensitivity to that antibiotic. They indicated that there was firm evidence that antibiotic-resistant strains of certain microorganisms such as E. coli and Salmonella species became established in animals that had—received antibiotics as feed additives or therapeutically. However, there were no sub stantial indications that bacterial resistance had interfered with therapy by a particular antibiotic.

Following agitation in the popular press and media, the Netherthorpe Committee met in January of 1966 and recommended that ''an appropriate body with sufficiently wide terms of reference should consider the evidence about the use of antibiotics in both animal husbandry and veterinary medicine and its implications in the field of public health'' (Braude 1978). In July 1968 the Ministers of Health and Agriculture, Fisheries, and Food appointed a joint committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine under the chairmanship of Professor M. M. Swann. In November 1969 the Swann Report was published. The main recommendations were that:

the supply of penicillin, chlortetracycline, and oxytetracycline without prescription should be revoked, and that of tylosin, nitrofuran, and sulfonamides should be available only on prescription;

"feed" antibiotics as defined by the Netherthorpe Committee should be available without prescription for pigs and poultry, and for calves up to 3 months of age, but not to laying poultry and adult breeding stock (the latter restriction was subsequently removed); and

"therapeutic" antibiotics should be available for use in animals only if prescribed by a member of the veterinary profession who has the animals under his care.

Antibiotic Use

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The Swann Report noted that in 1967, 240 tons of antibiotics were used in the United Kingdom for medical use and 168 tons for veterinary use, a 6:4 ratio (Braude 1978). If penicillin and tetracyclines were removed, the ratio was 8:2. In an independent survey the same year a ratio of 8.5:1.5 was obtained (Braude 1978). In the latter survey two-thirds of the 15 percent used by veterinarians was for therapeutic purposes (10 percent of the total) and one-third for growth promotion (5 percent of total). The ratio between medical and other uses of antibiotics was about 7.5:2.5 in 1975 (Braude 1978). The 25 percent used for nonmedical purposes was divided 70:30 for veterinary and growth promotion, respectively.

There is little indication that overall sales of antibiotics for veterinary use has decreased as a result of the Swann Report (Linton 1977a). The total usage of antibiotics in the United Kingdom has increased since the Swann Report (Table 4.1). There was no substantial increase from 1963 to 1967, but the amount essentially doubled (penicillins, tetracyclines, and feed antibiotics) by 1975 (Braude 1978). "Feed" antibiotics include those that are allowed to be used in the feed and include flavomycin (bambermycins), virginiamycin, and zinc bacitracin. In a recent controversial BBC program, "Brass Tacks," misuse of antibiotics by farmers was alleged (Anonymous 1979a). It was suggested that veterinary surgeons may over-prescribe.

Performance

There is no evidence that performance has been decreased as a result of the implementation of the recommendations of the Swann Report. However, antibiotics are still used in large amounts (Table 4.1) and substitutes such as copper sulfate have been introduced.

Resistance

Low-level antibiotic feeding has resulted in bacterial resistance (Linton 1977 a,b; Smith 1977a; Braude 1978; Richmond and Linton 1980). Large differences have been found in drug resistance of E. coli between animals fed and those not fed antibiotics. The resistance to antibiotics is transmissible. In many instances the resistance is due to the presence of R- plasmids. These R-plasmids are able to mediate their own conjugal transfer in addition to specifying resistance to certain antibiotics.

An outbreak of Salmonella typhimurium phage type 29 occurred in calves in Britain from 1963 to 1969 (Linton 1977b). Evidence was obtained indicating that the emergence of resistant S. typhimurium correlated closely with the increasing range of antibiotics used, and that resistant strains also caused infections in man. The evidence concerning antibiotic- resistant E. coli of animal origin reaching man is not complete. It was concluded that antibiotic-resistant E. coli in animals cannot be distinguished from those found in man. Transferable drug' resistance was demonstrated in chickens and calves, but not in pigs, by feeding large numbers of donor strains to these animals. Transfer of drug resistance to humans by feeding donor cells from animals or humans has not been substantiated.

Persistence of drug resistance has been related to the usage pattern of antibiotics (Linton 1977 a,b). Use of antibiotics in dairy herds for treating mastitis or as a prophylactic at the end of lactation had little or no effect on drug resistance in E. coli. In pigs, calves, and poultry, administration of antibiotics by the oral route for short periods resulted in high levels of drug resistance which soon decreased. Conversely, when antibiotics were fed continuously at subtherapeutic levels incidence of drug resistance was greater and persisted for a long period after the drug was discontinued. Continuous exposure appears to stabilize the resistant organisms, which become part of the flora of the gut

Richmond and Linton (1980) recently conducted studies to determine if the animal or human use of tetracyclines was quantitatively the more important source of resistant E. coli for man. They studied the amount of tetracycline prescribed in the County of Avon, England. By extrapolation they found that 3 percent of all prescriptions were for tetracyclines. They found that in hospitals tetracycline was used in 26 percent of all acute beds and 55 percent of all long-stay beds. It was concluded that at any one time 0.75 percent of the county's approximately 1 million inhabitants will be excreting tetracycline-resistant organisms as a direct result of tetracycline treatment. This figure compares favorably with the value of 3 percent of the coliforms in Bristol sewage found to be resistant to tetracycline. Furthermore, sewage from hospitals was found to contain a higher proportion of resistant R-factor-carrying strains of E. coli with multiple resistance than did domestic sewage (Linton 1977b). Richmond and Linton also obtained evidence that use of other antimicrobial agents such as sulfonamide may select indirectly for tetracycline resistance.

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Richmond and Linton (1980) stated "overall, therefore, it seems as though we must look to the medical, as opposed to the veterinary, use of tetracycline as the main selective pressure for the high incidence of tetracycline-resistant organisms in the human population, and the source of such organisms in human beings not receiving antibiotics is more likely to lie in human beings who are being treated than in the farm animal population." It has been suggested that "those doctors who criticize their veterinary colleagues for the indiscriminate and inappropriate use of antimicrobial agents in animals should pause awhile before casting their Stones" (Anonymous 1979b).

It has been reported that tetracycline-resistant Salmonella species in swine and humans have decreased in the Netherlands since 1973 (van Leeuwen et al., National Institute for Public Health, Bilthoven, the Netherlands, personal communication, 1979). This decrease coincides with the discontinued use of tetracycline as a feed antibiotic. However, in calves the number of type 505 isolates of S. typhimurium has remained constant and the number of multiple resistant phage type 201 has increased.

In the United Kingdom there has been no change in the incidence of pigs excreting tetracycline-resistant E. coli (Braude 1978). No decrease in oxytetracycline-resistant E. coli in pigs was found in the United Kingdom from 1956 to 1975 (Smith 1977a). M. R. Richmond (University of Bristol, personal communication, 1979) stated that no reduction had occurred in the incidence of antibiotic-resistant E. coli in Europe following the implementation of regulations recommended in the Swann Report.

The Scientific Committee for Animal Nutrition was set up by the Commission of the European Communities to provide informed opinions on matters pertaining to animal nutrition and effects of production methods on food quality and the environment. A series of reports was prepared by the Scientific Committee for Animal Nutrition (1978) related to antimicrobials. Three of the reports concerned antibiotics. The reports covered (1) The Use of Macrolides and Related Products in Feedingstuffs, (2) The Conditions of Use of Certain Antibiotics in Feedingstuffs, and (3) Use of Zinc Bacitracin and Flavophospholipol and Feedingstuffs for Laying Hens. The antibiotics covered in the reports were: oleandomycin, spiramycin, erythromycin, tylosin, lincomycin, virginiamycin, zinc bacitracin, and flavophospholipol. Use of penicillin and tetracyclines was not addressed.

Chapter 5. Effect on Animal Disease of Subtherapeutic Use of Antibiotics During the last 30 years, subtherapeutic levels of antibacterial drugs have been fed extensively in every major livestock and poultry producing country. The wide acceptance of antibiotics in low levels is attributed to their established benefits of improving feed conversion and growth rate and reducing the morbidity and mortality from subclinical and clinical diseases. During this same period, the poultry, swine, and beef cattle industries were able to develop large, highly intense production units by the use of antibiotics to control disease problems or to increase performance.

Subtherapeutic levels of antibiotics have been defined by the FDA as lower than the therapeutic levels needed to cure disease. This has arbitrarily been set at 200 g per ton of feed for chickens and/or swine and 11 mg/kg bodyweight per day for cattle (U.S. DHEW/FDA 1978).

It is unknown whether the activity of antibiotics used in low levels in animal feeds exerts its influence by: (a) metabolic effect, (b) nutrient sparing or increased absorption and utilization of nutrients, (c) activity against microorganisms, or (d) a combination of these activities.

Data presented by Hays (1978) indicated that the wise use of antibiotics is not a substitute for, but a complement to, good sanitation and husbandry for disease control.

Soon after the introduction of antibiotic agents, drug resistance in bacteria was observed. This phenomenon was also observed to occur spontaneously and in other stress situations. Under continuous antibacterial pressure such resistant organisms will become predominant (Smith 1967).

After 30 years of extensive use of antibiotics in animal feeds, discussions still deal with potential public health hazards. It is difficult to cite human health problems that can be attributed specifically to meat from animals fed antibiotics or that can be associated with direct or indirect contact with animals fed low levels of antibiotics. The evidence that resistant organisms in animals compromise the treatment of diseases in man or animals is sparse, indirect and difficult to evaluate.

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A general decrease in the cost of antibiotics has encouraged the use of higher levels than were commonly used several years after the growth promoting effects of antibiotics were first discovered. The levels selected at that time were not levels that elicit maximum response. Generally they were compromised levels based upon a cost/benefit ratio.

The possible hazards to animal health from using antibiotics in low levels are: (1) adverse or toxic reactions in the animal, (2) development of resistant strains of pathogenic organisms, and (3) increased susceptibility to some infections through immunosuppression or alteration in the microflora.

Toxicity is usually not a problem in food animals from the use of antibiotics. When such problems occur, they are usually traced to human error, i.e., the misuse of the drug for purposes not included on the label or mixing errors.

There is likelihood that antibiotic utilization has been abused both in animal and human medicine. It has been shown that the use of subtherapeutic and therapeutic levels of antibiotics does in fact cause resistant strains of organisms to emerge. This may make it necessary to change drugs when treatment is not effective for the first drug of choice. As in man, there is no way to know what role the use of antibiotics in animal feeds at the subtherapeutic level has on the establishment of resistant populations of bacteria when compared to the therapeutic use of antibiotics.

Salmonella species are widespread in nature and frequently cause food poisoning in humans. Epidemiological studies show that foods of animal origin are frequently involved. Salmonellosis in humans involving antibiotic-resistant strains of bovine origin has occurred (Anderson 1968, Threlfall et al. 1978). Although the disturbances occurred under conditions of widespread antibiotic use, there is no evidence of any relationship to subtherapeutic feeding. These studies are not generally complete enough to determine the source of contamination. It is difficult to determine whether or not these foods were contaminated before or after slaughter or if the last vector was a food handler. It is doubtful that restricting antibiotic levels in animal feeds will cause a reduction in food-borne infections of humans.

Up to the mid-1960's, before antimicrobial resistance became recognized as a result of widespread use of antibiotics, the compromising effect of subtherapeutic antibiotic administration was repeatedly registered. Smith (1967) wrote "it is becoming increasingly apparent that the frequent prophylactic and therapeutic use in a pig herd of any of the available antibacterial drugs eventually results in penicillin drugs becoming largely ineffective in the treatment of E. coli infections." He also documented the development of penicillin resistance in 60 percent of staphylococcal strains in arthritis in chickens on diets containing penicillin and tetracyclines. Arthritis outbreaks in years prior to antibiotic feeding yielded strains susceptible to penicillin. More recently, Hjerpe (1976) reported a decline in response to tetracycline therapy by pneumonic cattle simultaneous with a rise in prevalence of tetracycline, penicillin, and sulfonamide-resistant strains of Pasteurella species after feeding of subtherapeutic levels (100 g/ton) of chlortetracycline was initiated in a feedlot.

The general rise in antibiotic resistance among bacteria during the past 30 years of intensive antibiotic use has undoubtedly curtailed the usefulness of some previously effective drugs. Documentation concerning this development is scarce, and the extent of it ascribable to subtherapeutic use of antibiotics is impossible to determine.

Chapter 6. Therapeutic Use of Antibiotics

Background

Infectious diseases constitute the largest single category of medical problems in the several species of domestic animals. As a result, veterinarians have had a critical need for the anti-infective drugs in the course of everyday practice. Prior to the introduction of modern antibiotics, metallo-organic compounds, various antibacterial dyes, and other chemotherapeutic agents were employed. Shortly after sulfonamides were introduced in the late 1930s, they were recognized as being effective against bovine mastitis, and soon after against a wide spectrum of other bacterial infections of animals. Similarly, introduction of the various forms of penicillin soon led to their broad application in all species of domesticated and zoo animals. As the antibiotic era developed, each new addition to the antibiotic roster, such as the tetracyclines, chloramphenicol, bacitracin, streptomycins, neomycin, kanamycin, gentamicin, polymyxin, griseofulvin, nystatin, amphotericin B, erythromycin, tylosin, lincomycin, clindamycin, cephalosporins, and the semisynthetic penicillins soon found a valued position in veterinary medicine.

In-depth surveys (1967, 1972 to 1975) of the therapeutic usage of various classes of drugs in veterinary medicine have been reported from the University of Minnesota College of Veterinary Medicine. There, workers have, over the past years,

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surveyed the frequency of total drug usage in both large and small animals, including the categories of companion, zoo, and food-producing species (Stowe 1975). These studies clearly revealed that antibiotic drugs were the most frequently used agents in the treatment of animal disease. The studies involved the sampling of 5 percent of the clinical cases that were presented to the Veterinary Teaching Hospitals, including the out-patient and in-patient Large and Small Animal Hospitals and a rural outlying food-animal practice. In terms of the total number of drug treatments (many animals received more than one drug) the most frequently employed classes of drugs were as follows: antibiotic agents, 48 percent; anthelmintics, 15 percent; corticosteroids and other endocrine agents (exclusive of diethylstilbestrol), 12 percent; fluids and electrolytes, 7 percent; analgesics, anesthetics, and tranquilizers, 6 percent; and gastrointestinal agents, 5 percent; with the remainder scattered among the autonomic, cardiac, antihistamine, topical, and miscellaneous categories. While this survey dealt only with one large teaching hospital in the upper Midwest, frequent contacts with comparable institutions elsewhere and with both large and small animal practitioners leaves little doubt that infectious diseases constitute the largest single category of disease problems, and that antibiotic drugs are the most frequently employed agents.

Within the category of antibiotic agents, the most frequently employed drugs are the penicillins (including the broad spectrum derivatives such as ampicillin and the penicillinase-resistant penicillins such as cloxacillin, dicloxacillin, etc.) and the tetracyclines, particularly oxytetracycline. In addition to these ''mainstays" which continue to be effective and serviceable in the majority of cases, the sulfonamides continue to be heavily used because of their efficacy in the frequently encountered pasteurellosis infections in cattle and sheep. Tylosin, a nonhuman anti biotic, is also very heavily employed. In general, the economics of livestock production is a significant determinant in deciding which antibiotic agent to employ: the newer antibiotics tend to be more costly, a fact that makes their routine use in food animals uneconomical. In companion animals, on the other hand, including horses, the cost of medication is often not a major consideration, and thus erythromycins, cephalosporins, gentamicin, and sulfonamide-trimethoprim combinations are more frequently employed.

In terms of efficacy and safety, there can be little doubt that the antibiotic drugs are essential therapeutic agents in the diseases of domestic animals.

The widespread usage of veterinary services in the livestock industry points to a very real economic gain to the producer when veterinary services are utilized. In a series of studies sponsored by the Minnesota Agricultural Experiment Station, the World Bank, and the U.S. Department of Agriculture, it was found that there is a strong positive correlation between the use of veterinary services, the health of livestock, and the net income from the farm operation (McCauley 1974 a, b). In view of the major use of antibiotic drugs in veterinary practice, it would seem reasonable to infer that these drugs constitute a significant contribution to livestock production and economics.

From time to time, infectious diseases do not seem to respond to treatment with a particular antibiotic drug. In such instances either the dosage is increased, or another antibiotic agent is selected. In most cases, when therapy with an appropriate drug is initiated early in the course of the disease, the outcome is ultimately successful. However, when faced with therapeutic failure, some veterinarians conclude that their initial selection was unsuccessful because of prior use of low-level feeding of antibiotic substances to a herd or flock. A few practitioners declare that the problems they perceive as drug failures can be attributed to low-level antibiotic feeding. When queried in detail about their justification for such statements, proof is lacking. Carefully controlled studies regarding the cause-and-effect relationships between antibiotic feeding and subsequent therapeutic failures are lacking. Certainly veterinary practitioners, whether rural or urban, are not equipped to undertake the in-depth studies required to establish or refute the point at issue and consequently their opinions, no matter how firmly expressed, have to be rejected due to lack of scientific evidence. It is self-evident that perceived therapeutic failures could be due to factors such as misdiagnosis, inadequate dosages, antibiotic drug antagonisms, and others.

In some of the larger group practices and at the veterinary teaching institutions, antibiotic drug sensitivity tests are employed quite routinely. Lack of susceptibility or resistance to standard concentrations of various antibiotic drugs is encountered to a varied degree with all drugs, including those that have not been used at all, or used only to a minimal extent for low-level antibiotic feeding (i.e., cephalosporins, chloramphenicol, gentamicin, kanamycin). Moreover, the validity of in vitro sensitivity testing has sometimes been questioned. Clinicians have reported therapeutic successes in treating infections due to agents shown to be resistant by laboratory tests (C. M. Stowe, University of Minnesota, College of Veterinary Medicine, personal communication, 1979). This general observation is further buttressed by comparing the apparent frequency of in vitro nonresponsiveness in the hospitalclinic setting to that which one obtains in the farm setting,

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where the frequency of nonresponsive organisms seems to be lower despite the juxtaposition in the latter case to low-level antibiotic feeding.

The use of data gathered from veterinary teaching hospitals and clinics regarding the frequency of resistance among pathogens may not be an accurate reflection of the true level of resistance in specific regions of the country or in the nation at large. Be fore any inferences are drawn regarding the degree or frequency of resistant animal pathogens, we need to have more in-depth knowledge of the spectrum, scope, and degree of antibiotic resistance that is representative at least in the domestic animal population. At pre sent there simply is no body of incontrovertible evidence regarding the relative importance of the human as a source of resistant organisms in animals or of animals as a source of resistant organisms in man. Furthermore, it would be impossible at the present time to say whether the resistant organisms arose as a result of subtherapeutic antibiotic feeding, prophylactic use, or therapeutic use for the treatment of a specific disease outbreak.

Control and Regulation

Control and regulation of the therapeutic use of antibiotic drugs is under the purview of the FDA, particularly the Bureau of Veterinary Medicine and the Bureau of Foods. Control is exercised through the mechanism of the New Animal Drug Application (NADA). Once approval is granted and the drug is marketed, therapeutic use by veterinarians and in some cases by livestock producers follows. Such usage is based on the indications of the drug; the experience of the practitioner; and the inherent constraints of the dosage, route of administration, and the residue or withdrawal times. In the overwhelming majority of cases care is taken to observe the requirements of proper withdrawal times for either milk or meat.

From time to time, the question of auditing antibiotic drug usage arises, primarily within the setting of human hospitals. Other than in an institutional setting, the auditing of drug usage would be very time consuming, costly, and difficult to control.

Epidemiological Considerations

There is general agreement that the use of antibiotics in both animals and humans leads to increased frequency of antibiotic resistance. Furthermore, there is little doubt that resistance can be transferred through plasmids from certain resistant microorganisms to others that were originally sensitive. These in turn have been shown to be transmissible to other animals and, in isolated cases, to humans (Levy et al. 1976 a, b; Hirsh 1977). This resistance transfer or ''infectious drug resistance" has led on the part of some individuals, to the fear that resistant strains could be transferred to other animals and humans, thereby creating a reservoir of pathogens, which when involved in clinical infections, would be unresponsive to antibiotic treatment. While such fears may seem to be a logical extension of current knowledge regarding resistance, there is practically no information on the extent to which this is happening, nor is it clear in the case of the few such instances known whether they were due to low-level antibiotic feeding, therapeutic use of antibiotics in domestic animals (including companion and pet animals), or therapeutic or prophylactic use of antibiotic drugs inhuman beings. These vexing questions are not easily resolved, particularly in view of the fact that both humans and animals often share the same pathogens.

Chapter 7. Voids In Knowledge and Suggested Research Although voluminous research has been conducted regarding the effects of feeding antibiotics on performance, research has been very limited in certain other areas. Research results have shown that resistance of microorganisms exists in animals fed antibiotics and that this resistance can be transferred (Linton 1977 a, b; Smith 1977a). However, there is inconclusive evidence that the use of antibiotics as growth promotants compromises therapy of humans and animals. Few well-designed experiments have been reported, and clearly there is a need for well-designed intensive investigations of this important issue.

The main objectives of the proposed research to fill in the primary voids concerning antibiotics are to determine: (a) if the feeding of tetracyclines and penicillin compromise animal therapy, (b) the relation of antibiotic feeding to human health, and (c) the mechanism of action of antibiotics in growth promotion.

It is suggested that the research described in the following pages be undertaken.

Effect of Tetracycline Feeding On Animal Therapy

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Poultry And Swine

The possibility that administration of subtherapeutic levels of antibiotics may compromise therapy has not been adequately investigated. Most previous studies have given negative results with respect to this question, but according to the FDA (U.S. DHEW/FDA 1978) experiments generally were poorly designed. Carefully planned and controlled experiments conducted with poultry and swine should be conducted to attempt to answer this question with organisms such as Salmonella typhimurium. This organism should be used in these animals to determine whether development of resistant organisms will compromise treatment of a severe infection in the species. Chicks and swine should be inoculated with S. typhimurium to induce a lowlevel, nonlethal infection, and be fed diets with and without tetracycline. After a few weeks the animals will be challenged with an inoculum calculated to cause a severe infection resulting in considerable mortality. This inoculum should be isolated from animals fed antibiotic and should be documented to contain antibiotic-resistant organisms. The effectiveness of therapeutic levels of tetracyclines and other antibiotics against this infection should be determined. To avoid the problem of possible development of immunity, animals unexposed to the organism should also be inoculated with the dose to cause a severe infection, and the effectiveness of antibiotic therapy in these animals should also be investigated. Careful laboratory work to monitor development of antibiotic-resistant organisms in the animals and immunity development would be needed.

Cattle

Cattle in commercial feedlots should be studied that (a) have not received antibiotics; (b) have received a high level of antibiotic during the first 3 to 4 weeks, followed by a low level during the remainder of the period on feed; and (c) have received a high level of antibiotic during the first 3 to 4 weeks, followed by withdrawal of the drug. Comparisons should be made of tetracycline therapy on sick animals from the lots on the various treatments. Response to therapy should also be monitored by the number of animals treated, the length of stay in the sick pens, and mortality. Measurements should also include antibiotic susceptibility of organisms in treated animals and samples of healthy animals from all lots at periodic intervals.

This type of experiment will need to be performed in cooperation with university or USDA scientists and feedlots. It would be ideal for most of the feedlots to be in the California and Arizona area where antibiotics are not normally used. However, it would be important that some feedlots, at least those that are treated, be located in the Colorado or Kansas area, where a continuous level of feeding of tetracyclines is routinely practiced. It will be essential that the cooperating feedlots use only tetracycline as the subtherapeutic and therapeutic drug. It will be essential to reimburse the feedlots for death losses above the normal mortality rate caused by the experimental treatments. Also, some compensation will have to be made for the extra labor involved in handling the cattle, such as monitoring the normal animals for antibiotic-resistant organisms. The organisms used to monitor resistance will likely be a common species of Salmonella and E. coli.

Relation of Antibiotic Feeding to Human Health

The information which would be required to answer the controversial question will necessitate investigations of staggering complexity and cost. It is likely that broad-based studies will involve monitoring of health-related problems among human populations involved in and isolated from low-level antibiotic feed programs. Of course, when studying people involved with animals and animal products, animal health should also be monitored. Baselines must also be established by determining the history of the subjects with regard to antibiotic exposure and the susceptibility of the microflora species to antibiotics.

Recent experiments with animals have shown that randomly selected individuals already carry some resistant enteric microorganisms. It may be necessary to study respiratory bacterial flora instead of, or in addition to, the changes or lack of changes in susceptibility by species over a period of time and the nature of any disease episode particularly if suggestive of microbial etiology. The susceptibility of any agent thought to be involved would have to be established and the success of antimicrobial therapy determined clinically and microbiologically. The logistics and mechanics of this type of study will be extremely demanding in time and labor. Some aspects, especially those involving humans, would require several years, a large population, or both, for the collection of adequate data. If the microflora present at the onset is already predominantly resistant to the antimicrobials of interest, this study would be pointless.

Mechanisms of Action of Antibiotics In Growth Promotion

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"Growth promotion" from the low-level feeding of antibiotics refers to an improvement in both rate of gain and efficiency of feed conversion. Improvement normally occurs in both measures of performance but not necessarily to the same degree. In view of known factors that influence rate and efficiency of gain, antibiotic action affecting each measure of performance should prove to be, at least in some respects, different.

The different chemical nature, absorbability, and bacterial spectrum of growth promoting antibiotics suggest that the mode of action in growth promotion cannot be the same for all of the antibiotics that have proven efficacious. There is also good evidence that antibiotic action affecting growth in the different species is not entirely from the same mode of action. Factors involved are the complex mechanisms related to disease, feed intake, digestion, absorption, and metabolism of nutrients, as well as antibiotic effects on enteric flora and the systemic bacterial population.

In swine, frequent measurement of rate and efficiency of gain in control and antibiotic-fed animals reveals that a response to the antibiotic is not consistent but occurs only occasionally, and for what is usually a short period of time. Such an effect over an extended period promotes "average" performance above controls.

In view of this important temporary effect, studies are suggested in which short-term performance measurements (feed intake and rate of gain) are correlated with similar short-term measurements related to the microbiology and biochemistry of the different physiological systems in control versus responding animals. Intestinal cannulation to permit sampling of ingesta at different points in the tract, together with simultaneous blood measurements, are needed for such an approach.

Experiments designed to uncover mechanisms related to the growth-promotant effect might provide a means of exploiting these mechanisms other than by the use of feeding levels of antibacterial compounds.

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U.S. Bureau of the Census (1978) Census of Agriculture. Vol. II, Statistics by Subject: Livestock, Poultry, Livestock and Poultry Products, Fish. Washington, D.C.: U.S. Department of Commerce.

U.S. Department of Agriculture (1978) Economic effects of a prohibition on the use of selected animal drugs. Agr. Econ. Report No. 414. Economics, Statistics and Cooperatives Service. Washington, D.C.: U.S. Department of Agriculture.

U.S. Department of Agriculture (1979. a) Cattle on Feed Reports. Economics, Statistics, and Cooperatives Service. Washington, D.C.: U.S. Department of Agriculture.

U.S. Department of Agriculture (1979. b) Livestock and Meat Statistics. Economic Research Service. Washington, D.C.: U.S. Department of Agriculture.

U.S. Department of Health, Education, and Welfare/Food and Drug Administration (1972) The Use of Antibiotics in Animal Feeds. FDA Task Force Report, Bureau of Veterinary Medicine. Rockville, Md.: Food and Drug Administration.

U.S. Department of Health, Education, and Welfare/Food and Drug Administration (1978) Draft environmental impact statement: Subtherapeutic agents in animal feeds. Washington, D.C.: Food and Drug Administration, Bureau of Veterinary Medicine.

Van Arsdall, R. N. (1978) Structural characteristics of the U.S. hog production industry. Agr. Econ. Report No. 415, Economics, Statistics, and Cooperatives Service. Washington, D.C.: U.S. Department of Agriculture.

Warner, R. G. (1972) Antibiotics in veal calf and dairy replacement calf nutrition and disease control. Presentation before the FDA Task Force, Denver, Colorado, September 16-17, 1970.

Woods, W. (1970) Antibiotics in beef cattle nutrition disease control. Presentation before the FDA Task Force, Denver, Colorado, September 16-17, 1970.

Zimmerman, D. R. (1968) Antimicrobial feed additives for swine. A paper presented at the Annual Meeting of the Iowa Pork Producers, Des Moines, Iowa.

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Figures

Figure 2.1

Market structure of formula feed industry.

Source: Anonymous (1978).

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Tables

TABLE 2.1 Number of Farms with Pigs in the United States and Iowa and Total U.S. Production

Year Number of Farms with Pigs, United States

Number of Farms with Pigs, Iowa

Total U.S. Carcass Weight Produced (million pounds)

1954 1,424,000 136,800 12,002

1964 743,000 108,900 14,598

1974 450,000 66,300 14,331

SOURCE: U.S. Bureau of the Census (1974).

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a

TABLE 2.2 Number of Large-Volume Producers and size of Operation

Year Number of Operations Producing 2,500 to 4,999 Head/Year

Average Size of Operation

Number of Operations Producing 5,000 Head or More/Year

Average Size of Operation

1975 1,567 2,418 1,168 7,053

1978 1,661 3,196 1,340 10,192

A producer was included in this category if production was 2,500 head or more in any year included in the survey.

SOURCE: Stemme et al. (1978, 1979).

a

a

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a

TABLE 2.3 Feed Required to Produce a 250-1b Pig, Recommended Antibiotic Levels, and Consumption of Antibiotics per Pig (estimates)

Stage of Production

Pounds of Feed Required per 250-1b Pig

Recommended Antibiotic Level (mg/1b diet)

Estimated Use (mg/1b diet)

Grams per Pig

Breeding Boar 15 ——— Trace ———

Bredding Sow

Pregnancy 150 ——— 5.0 0.75

Lactation 60 50b 25.0 1.50

Starter 25 100-125 100.0 2.50

Grower 50 50 25.0 1.25

Finisher 800 1-25 12.5 10.00

Total 1,100 16.00

For pregnancy, recommendations would include an antibiotic at a high level (1.0 g/day) during the breeding period, about 20-25 days. Not all sows would be fed an antibiotic.

Since response to antibiotics fed to the lactating sow are not consistent, no general recommendation is made for their inclusion by experiment stations.

SOURCE: V. C. Speer, Iowa State University, personal communication, 1979.

a

b

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a

TABLE 2.4 Summary of Changes in Net Farm Income and USDA Food Market Basket from Banning All Subtherapeutic Use of Animal Drugs, First and Fifth Year after Ban

First Year Fifth Year

Farm Income 5

Moderate Drug Efficacy

Change in billion dollar +1.2 -0.5

Change in percent +4.7 -2.1

High Drug Efficacy

Change in billion dollars +2.8 -0.9

Change in percent +2.8 -3.81

Food Market Basket:

Base (dollars) 2,132 2,530

Moderate Drug Efficacy

Change in dollars +32.0 +5.0

Percent change from base +1.5 +0.2

High Drug Efficacy

Change in dollars +99.0 +16.0

Percent change from base +4.6 +0.7

The market basket is the average quantities of domestic farm-origin foods purchased annually in retail food stores per urban household.

SOURCE: USDA (1978).

a

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a

TABLE 2.5 Effects of Banning Selected Antibiotic and Drug Feed Additives on Annual Consumer Expenditures for Meat

Estimated Annual Consumer Costs

Option Per Capita ($) Nationally (billion $)

Ban tetracyclines and penicillin 5.70 1.2

Ban nitrofurans and sulfa 12.00 2.6

Ban all of above 19.00 4.1

It is assumed that substitute antibiotics will be available, mainly tylosin and bacitracin.

SOURCE: Headley (1978)

a

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Table 3.1 Experimental Antibiotic Responses for Swine

Percent Improvement

Years Number of Experiments

Feeding Period Rate of Gain

Feed/Gain Author

1960- 1967

8 Baby pigs (<100 g/ton antibiotic) 36.0 13.5 Zimmerman (1965)

1960- 1967

7 Baby pigs (>100 g/ton antibiotic) 49.5 13.2 Zimmerman (1968)

1965- 1970

20 Baby pigs (8-20 1bs) 35.7 15.6 Teague (1971)

1965- 1970

6 Young pigs (22-42 1bs) 5.1 9.0 Teague (1971)

1950- 1977

378 Young pigs (<35-80 1bs) 16.1 6.9 Hays (1978)

1950- 1953

165 Growing pigs (30-50 1bs) 8.7-15.0 2.6-7.8 Braude et al. (1953)

1965- 1970

7 Growing pigs 9.0 1.4 Teague (1971)

Finishing pigs (same pigs) 6.7 0.1

1950- 1977

276 Growing pigs (35-80 1bs) 10.8 4.5 Hays (1978)

1950- 1963

9 Growing-finishing 9.0 2.9 Melliere and Waitt (1971)

Growing-finishing (no antibiotic during finishing)

6.2 1.2

1950- 1977

279 Growing-finishing (32-207 1bs) 4.0 2.1 Hays (1978)

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TABLE 3.2 Effect of Antibiotics on Farrowing Rate

Farrowing Rate (%)

Drug Number of Sows Control Treated

Chlortetracycline 179 62 79

Chlortetracycline 198 74 86

Aureo SP-250 96 81 96

Aureo SP-250 126 53 56

Aureo SP-250 79 30 36

Tylosin 192 75 77

Tylosin 143 81 84

Tylosin-Sulfamethazine 197 70 83

Furazolidone 87 63 93

Chlortetracycline 249 67 75

Chlortetracycline 239 71 72

Aureo SP-250 184 61 70

Chlortetracycline 101 90 94

SOURCE: V. C. Speer, Iowa State University, personal communication, 1979.

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TABLE 3.3 Experimental Antibiotic Responses for Poultry

Comparison Comparison

Species or Type of Bird

State of Growth or Production

Number of Comparisons

Control Antibiotic Percent Improvement

Number of Comparisons

Control Antibiotic Percent Improvement

Weight (grams) Feed/Gain

Chick Hatch to about 4 weeks

565 382.0 407.7 6.72 313 2.03 1.94 4.43

Chick Hatch to about 8 weeks

286 1,313.0 1,351.6 2.94 219 2.42 2.36 2.48

Egg Production (%) Feed/Dozen Eggs (1bs)

Hens Egg production

244 59.9 62.3 4.01 122 5.30 5.05 4.72

Hatchability (%)

Hens Breeders 69 76.2 78.8 3.41

Weight (grams) Feed/Gain

Turkeys Hatch to about 4 weeks

166 489.0 554.0 13.29 76 1.86 1.73 6.98

Turkeys Hatch to about 8 weeks

126 1,963.0 2,101.0 7.03 100 2.08 2.00 3.85

Weight (1bs)

Turkeys Hatch to market weight

85 19.80 21.22 7.17 77 3.18 3.12 1.89

Egg Production (%) Feed/Egg (grams)

Turkeys Breeders 15 44.2 44.8 1.36 9 516.00 483.00 6.40

Hatchability (%)

Turkeys Breeders 16 70.0 70.0

SOURCE: Adopted from Hays (1978).

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1 2

TABLE 3.4 Cattle Feeding Trials with Chlortetracycline

Number of Trials Comparisons Percent Improvement Source

Control Antibiotic

Daily Gain (1bs)

16 2.17 2.29 5.82 U.S. DHEW/FDA (1972)

Feed/Gain

21 10.2 9.7 4.22 U.S. DHEW/FDA (1972)

Liver Abscess Incidence (%)

8 41.5 15.9 -61.8 U.S. DHEW/FDA (1972)

Daily Gain (1bs)

34 2.33 2.43 4.3 Rapid gaining animals Burroughs et al. (1959)

31 1.42 1.50 5.6 Slower gaining animals Burroughs et al. (1959)

Feed/Gain

34 10.34 9.96 3.7 Rapid gaining animals Burroughs et al. (1959)

31 12.31 11.45 7.0 Slower gaining animal Burroughs et al (1959)

Only trials in which <100 mg CTC/head/day was fed Reduction

1

1

1

2

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a

TABLE 3.5 Calf Feeding Trials with Chlortetracycline

Number of Trials Comparison Percent Improvement

Control Antibiotic

Daily Gain (1bs)

16 1.16 1.38 19.0

TDN/Gain (1bs)

10 2.16 1.96 9.3

Only trials in which <100 mg CTC/head/day was fed.

SOURCE: U. S. DHEW/FDA (1972).

a

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TABLE 4.1 Usage of Antibiotics as Feed Additives (kg of active ingredients)

Year Penicillins and Tetracyclines "Feed Antibiotics

1963 40,983

1964 37,188

1965 35,205

1966 36,460

1967 41,680

1971 20,000

1973 19,000

1974 22,000

1975 26,500 55,000

SOURCE: Braude, R. (1978) Antibiotics in Animal feeds in Great Britain. Reprinted by permission of Journal of Animal Science 46:1425

Copyright © National Academy of Sciences.

Bookshelf ID: NBK216502

4/6/2021 Why Patent Protection In The Drug Industry Is Out Of Control

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Healthcare

Why Patent Protection In The Drug

Industry Is Out Of Control

Jan 19, 2017, 09:00am EST

Robert Pearl, M.D. Contributor

This article is more than 4 years old.

In the United States, the patent protection process as it relates to the drug industry has

been distorted by the political system, intense lobbying and large campaign contributions.

The result has been pricing contrary to the greater good of the nation.

Patents originated in ancient Greece. This legal protection assumed greater importance in

15th-century Venice as a means to protect the nation-state's glass-blowing industry. The

first patent granted in the United States was in 1790.

Across history, governments created patents for two important purposes. The first was to

stimulate interest in research and find solutions to problems that vexed the nation and the

world. The second was to promote the broader good of the country. The duration of time

designated for exclusive use of the new technology or approach was intended to be

relatively short, with the public gaining the resulting benefits in perpetuity. As such, the

granting of a patent was designed to advance not only the interests of its creator, but also,

equally, the economy and well-being of the nation.

The intent of the patent process and the balance

between the dual objectives have been warped

over the past decade. Increasingly, drug

companies are not investing in R&D

proportional to the profits they earn from the

drugs they bring to market, despite their protests

to the contrary. Instead, many have figured out

that it’s simpler and safer from a financial

perspective to either buy the rights to drugs developed by others and raise the prices many

times over, as with Sovaldi, or to obtain a medication already in existence and, using

monopolistic control, raise the price as much as 500% or more, as in the case of the

EpiPen. As a consequence, the patent protection process now primarily serves the drug

companies, most often not on behalf of the American people, but, rather, at their expense.

What Patents Originally Intended

Photo by TheDigitalWay/CC0

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Patent protection was never intended for use in a situation when human life would be

endangered through its use. In other areas of society, broad legal prohibitions exist to

protect human life and the well-being of citizens. For example, individuals are prohibited

from yelling "Fire!" in a theater, and utility monopolies that control all of the electricity

for a city are prohibited from price gouging. Patents make sense in a retail or

manufacturing context. If you don't want to purchase Venetian glass, you can decide it’s

too expensive. In contrast, if your child is born with a genetic defect, you have no choice

but to obtain the medication available for treatment regardless of price.

Patent protection effectively grants the pharmaceutical industry a monopoly, regardless of

the human consequences. For a patient with a particular disease and a single solution

available in the form of a sole-source drug, allowing exorbitant pricing that prevents

access for individuals to the medication runs counter to the expectation of Congress to

protect the health of its citizens.

The tension between the individual inventor and the population over what constitutes a

reasonable length of protection for intellectual property has played out in countries

around the world for centuries. Ultimately, however, a patent is not an intrinsic or

Constitutional right, but a conscious choice by governing bodies to grant the exclusive

ownership of rights to innovators based, as mentioned, on what’s best for all of the

citizens of the nation.

Our nation must achieve a thoughtful balance between the use of patent law to encourage

drug companies to develop new medications for diseases that can't be treated today and,

at the other end of the scale, the needs of patients to benefit from those drugs without

bankrupting either themselves or state and federal budgets. Prices should bear a

reasonable and logical relationship to the cost of development in return for protection

against competition. And while it's important that drug developers have a reasonable

profit incentive to stimulate innovation, we need as a society to insure that such incentives

optimize the right kinds of research and development, and not only the most potentially

profitable products. We are nowhere near that optimal point today.

Compounding Legal Problems

Complicating the problem are two pieces of legislation pushed by big pharma that further

distort the current pricing process. First, the prohibition on importing drugs from other

countries allows pharmaceutical companies to continue to discriminate on an economic

basis against patients in the United States. Second, the federal government is restricted

from negotiating prices on behalf of U.S. citizens, unlike governments around the rest of

the globe, thus guaranteeing Americans will pay more. As a result, our nation uses

approximately 40% of the drug products manufactured but funds two-thirds of the profits

generated by these global conglomerates.

The need for reforms to deal with drug pricing has not been lost on the president-elect. In

his first news conference, he highlighted the excessively high drug pricing that exists, and

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the negative effect it has on U.S. jobs and income.

What’s The Answer?

The next big wave of opportunities for the pharmaceutical industry will be the large-

molecule biological medications. These hold promise for the treatment of pain, arthritis,

cancer and Alzheimer's disease. Although these drugs have complex chemical structures,

their processes for production are becoming increasingly common. And yet, the drug

companies adopt the mindset that the price tags can be $100,000 a year and up. Even a

drug like insulin, used by millions of people with diabetes in the United States, is being

held hostage by the regulatory and approval process. In the United States today, insulin

can cost $100 for a single syringe, while the price in other countries is less than 10% of

that.

Drug companies, often deploying individuals and patient groups affected by a disease as

their advocates, have pushed for expedited approval for new medications. But if we want

to help people and make healthcare more affordable, we need an even more rapid process

for approval of biosimilars and generics.

Patents were originally intended to encourage innovators and maximize the greater good.

But today that privilege is being abused. Depending on what happens with legislation

enacted by the new Congress to modify the Affordable Care Act, this corruption of the

patent privilege could harm tens of millions of Americans who today are protected

through their healthcare insurance programs.

The time has come to return to the fundamental intent of the patent process. Patent laws

should promote and reward progress, while simultaneously maximizing the good of all.

When it comes to the drug industry today, the rewards for pharmaceutical companies

exceed the benefits to our nation. Hopefully, Congress and the new president will restore

the proper balance.

Follow me on Twitter or LinkedIn. Check out my website or some of my other

work here.

Robert Pearl, M.D.

I’m passionate about transforming the American healthcare system and helping people understand the

consequences of their medical decisions. I previously served as CEO of… Read More

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INTEGRIS BAPTIST MEDICAL CENTER AND INTEGRIS HEALTH INC. - $12.2 MILLION

SCIENCE APPLICATIONS INTERNATIONAL CORP. (SAIC) - $11.75 MILLION

CA TECHNOLOGIES - $11 MILLION

METPATH AND UNILAB CORP. - $11 MILLION

4/6/2021 Top Whistleblower Cases - $12.3 Billion Recovered - Phillips & Cohen

https://www.phillipsandcohen.com/successful-cases/ 11/13

CORNING CLINICAL LABORATORIES, UNILAB CORP. - $11 MILLION

ZWANGER-PESIRI INC. - $10.5 MILLION

ROTECH HEALTHCARE - $9.95M

DAMON CLINICAL LABORATORIES - $9.8 MILLION

TENET HEALTHCARE CORP. - $9.75 MILLION

KPMG - $9 MILLION

U.S. RENAL CARE - $7.3 MILLION

FLORIDA RADIOLOGIST - $7 MILLION

HEWLETT PACKARD AND AGILENT TECHNOLOGIES - $7 MILLION

GROUP HEALTH COOPERATIVE (KAISER FOUNDATION HEALTH PLAN OF WASHINGTON) - $6.3 MILLION

4/6/2021 Top Whistleblower Cases - $12.3 Billion Recovered - Phillips & Cohen

https://www.phillipsandcohen.com/successful-cases/ 12/13

SHARP MEMORIAL HOSPITAL - $6.2 MILLION

BERKELEY HEARTLAB/QUEST - $6 MILLION

PROVIDIAN FINANCIAL CORP. AND TOTAL SYSTEM SERVICES - $6 MILLION

CSX TRANSPORTATION - $6 MILLION

OMNICARE INC. - $5.3 MILLION

LOCKHEED MARTIN - $4.4 MILLION

HUGHES AIRCRAFT - $4 MILLION

AMERICAN SYSTEMS, ANIXTER AND CORNING - $3 MILLION

CYPRESS PHARMACEUTICAL AND HAWTHORN PHARMACEUTICALS - $2.8 MILLION

SINGULEX INC. - $1.5 MILLION

4/6/2021 Top Whistleblower Cases - $12.3 Billion Recovered - Phillips & Cohen

https://www.phillipsandcohen.com/successful-cases/ 13/13

EV3 (MEDTRONIC) - $1.25 MILLION

GILBANE BUILDING CO. - $1.1 MILLION

ROCKY MOUNTAIN INSTRUMENT CO. - $1 MILLION

4/6/2021 The Danger Of Loosely Regulated Supplements | American Council on Science and Health

https://www.acsh.org/news/2017/03/30/danger-loosely-regulated-supplements-11070 1/3

Dr. David Seres Photo: Truth in Advertising

The Danger Of Loosely Regulated Supplements

(/pro�le/david-seres) By David Seres (/pro�le/david-seres) — March 30, 2017

How would you feel about unlicensed pilots �ying commercial airliners? Or consider if we allowed every driver to determine which side of the street to drive on. Irrespective of your political leanings, there are times when federal regulations might be reassuring, and a loss of these regulations might give one pause.

While we’re at it, how would you feel about the federal government striking down all regulations that require that drugs are safe, contain what they claim, and actually work before going to market? This, and worse, is what happened in 1994, when the Dietary Supplement Health and Education Act was enacted.

“But wait,” you say, “dietary supplements are not drugs. They are just supplements. They are natural nutrients that

are good for you. Aren’t they?” A bit of an explanation is in order.

More is not necessarily better

First, anyone taking a dietary supplement is doing so to improve his or her health. Unless the supplement has a magical quality, the supplement must have a substance in it that has a bene�cial e�ect on the body. The active ingredients in supplements that have e�ects on the body are chemicals. When you take chemicals to impact health, we call these pharmaceuticals.

Simply because these are unregulated, do not come from P�zer or Merck, and are derived from plants, does not in any way guarantee safety or e�cacy.

Moreover, while it’s possible that the substances in the supplement may have a bene�t when taken in higher doses, it is even more probable that the substances in a supplement can be harmful or frankly, deadly.

Take green tea for example. Green tea has chemicals (polyphenols) that actually block the breakdown of fat in the intestine. This in turn decreases the absorption of fat, which decreases the calories absorbed. In theory, blocking fat absorption might help with weight loss. People who drink green tea a cup at a time over the course of the day are likely to have no problems.

Several dietary supplements made from green tea are on the market. Based on the theory on which supplementation is driven, which is “if some is good, more must be better,” then what is the harm if each pill contains the equivalent of 10 to 12 cups of tea? Well, there are now more

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than 40 reported cases of liver failure (http://acgcasereports.gi.org/�les/2014/07/13-0190.R1- Whitsett-Proof.pdf) in people who took green tea supplements. In fact, 20 percent of drug- related liver injuries are due to dietary supplements (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293199/). Drinking green tea all day provides small levels of the chemicals in the tea, and there is no signi�cant toxicity.

However, scientists believe taking a pill with 10 or 12 times that amount raises blood levels high enough to destroy the liver in some people. The risk that the concentration of something normally safe in food will become dangerous in a supplement is the risk with any extract sold as a dietary supplement. People have died as a result.

The claim game

Not only does the law allow for marketing of pharmacological products without proof of safety, it allows supplement manufacturers to make what amount to outrageous and misleading claims without proof of e�cacy. The regulations even provide for the wording to do so. The manufacturers must make their outrageous claims with great care. Fraud laws still apply. Nevertheless, by using wording such as “supports (heart, brain, muscle, bone, digestive, etc.) health” the supplement industry can suggest bene�t without really making direct claims.

Here’s how this works. If a substance is necessary for normal body functioning, and a de�ciency will cause harm, one can say that the substance supports the health of that organ or system. This does not mean that excess amounts will have any bene�ts. Take zinc as an example. Severe zinc de�ciency will cause your skin to fall o�, your ability to taste to diminish, and your immune system to function less well. Thus, zinc supports skin and immune health, as well as taste function.

Nevertheless, there is absolutely no proof that supplemental zinc, in the absence of a de�ciency, boosts immunity. Wine experts do not enjoy their cabernet more by taking zinc. Skin health is not improved with supraphysiological zinc doses. In fact, because zinc supplementation inhibits copper absorption and copper is also critical for skin health at normal levels, supplementing zinc may have a deleterious impact on healing. Please do not take this to mean that you should continue the zinc and add copper.

Natural may not equal safe

Just because something is natural does not make it safe. Snakebites will kill you. Botulinum toxin is the most deadly substance known. If you care about your health enough to take a pill, elixir, nostrum, or potion, you should care enough to want to be sure that the substances in it are at least safe.

When looser regulations and funding cuts for federal agencies are in vogue, it gives one pause to imagine that snake oil can be marketed without consequence. Currently, the only way we regulate what goes into supplements is through fraud or tort laws. These are enforced through the Federal Trade Commission (FTC) and state attorneys general, and not by the Food and Drug Administration (FDA). The FDA regulates drugs, but can only in�uence supplement manufacturers through guidelines on manufacturing practices.

4/6/2021 The Danger Of Loosely Regulated Supplements | American Council on Science and Health

https://www.acsh.org/news/2017/03/30/danger-loosely-regulated-supplements-11070 3/3

In the case of fraud, the Federal Trade Commission is the agency that should have the resources to take on these companies. Imagine the cost of doing the research to go after a company that has supplements with hundreds of di�erent ingredients and almost as many claims of bene�t. However, the FTC is already operating on a shoestring budget, as are state attorneys general. Alternatively, non-governmental foundations or attorneys may bring class- action suits for fraud. However, these are similarly extremely expensive and complicated. Finally, someone hurt or killed by a supplement might sue for damages. This, too, is expensive and harm is di�cult to prove.

While the government is shrinking, consider how we can protect ourselves from the $40-50 billion industry that dietary supplements have become, especially when they give six-�gure donations to politicians. For supplements, more regulation is needed, not less.

Reposted from Truth In Advertising (https://www.truthinadvertising.org/danger-loosely-regulated- supplements/)with permission, March 27, 2017

4/6/2021 Supreme Court lets pay-to-delay ruling against pharma stand

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C

Supreme Court lets pay-to-delay ruling against pharma stand

By Ed Silverman1 2 Nov. 7, 2016

APStock

ash is not always king.

In a move that should settle a highly contentious legal issue, the US Supreme Court on Monday declined to hear an appeal4 of a ruling5 that said cash payments are not the only litmus test for determining whether a patent settlement between drug makers deserves antitrust scrutiny.

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The case focused on a so-called pay-to-delay deal between Teva Pharmaceuticals and GlaxoSmithKline. In these arrangements, a brand-name drug maker reaches a settlement with a generic rival in exchange for ending patent litigation and an agreement for launching a copycat medicine at a future date. The Federal Trade Commission has argued the deals are anti-competitive and cost Americans about $3.5 billion annually in higher health care costs.

A 2012 decision6 by the Supreme Court, however, left open to interpretation whether a cash payment was the only sort of arrangement that generated antitrust concern. Drug makers have argued the ruling limited the decision to only cash payments. But the FTC and insurers have maintained that cash is not the only form of payment that has value and warrants antitrust review. The US Solicitor General agreed in a brief7 filed last month.

Legal experts say the decision by the Supreme Court should settle the matter.

“Sometimes, the refusal to hear a case is as important as a judicial opinion,” said Michael Carrier, a Rutgers University law professor who specializes in intellectual property, who was one of 53 professors who had filed a brief two years ago urging the appeals court to decide that cash is not the only form of payment that should generate antitrust worries.

“This denial is very important, because it ensures that the courts are completely consistent that payment extends beyond cash to encompass authorized generic deals,” he explained. “The FTC and private plaintiffs will challenge these deals, with today’s denial paving the way for continued scrutiny. … The issue may be over.”

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As we noted previously, Teva sought to make a generic version of Lamictal, a drug used to treat epilepsy and bipolar disorder, which prompted Glaxo to file a patent infringement lawsuit. The drug makers later reached a deal, but Glaxo did not make a cash payment to Teva. Instead, Glaxo agreed to allow Teva to sell generic chewable and tablet forms of Lamictal before its patent expired.

Moreover, Glaxo also agreed not to sell its own so-called authorized generic version of Lamictal, which would have competed with a version sold by Teva. This was the central issue, because payers that filed their own lawsuit against the drug makers charged the settlement was unfair. How so? They maintained the deal paved the way for higher prices than if Teva had proceeded to sell a lower-cost generic.

Two years ago, a federal district court judge ruled there was no reason for concern over antitrust behavior. But last year, the US Court of Appeals for the Third Circuit disagreed, which prompted Glaxo to seek a Supreme Court review. The drug maker was supported, by the way, by the trade groups for both brand-name and generic companies.

A key industry argument has been that patent settlements benefit the public because they resolve what might otherwise become lengthy litigation that delays the arrival of lower-cost generics. In seeking Supreme Court review, Glaxo argued4 that, if the appeals court ruling is allowed to stand, it would have a chilling effect on patent settlements and would become the “de facto national standard.”

“Ordinarily the Court stays out unless there is a split among the lower courts. Here, there is no split,” said Scott Hemphill, a New

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York University law school professor who specializes in antitrust and intellectual property issues. “Courts have generally held that payment is not limited to cash. That makes sense, because otherwise the rule against cash payments would be trivial to evade. Unless another court of appeals comes out differently down the line, it would be surprising for the court to take up this issue.”

A Glaxo spokeswoman wrote us that the company is “disappointed” by the Supreme Court decision and plans to move forward with the case at the trial court level. “We continue to believe that settlements like this one are pro-competitive because they allow parties to resolve expensive, business-disrupting litigation and permit competition consistent with federal and state antitrust laws,” she wrote.

We also asked the Generic Pharmaceutical Association for comment and will pass along any reply. A spokesman for the Pharmaceutical Research and Manufacturers of America, the trade group for brand-name drug makers, which filed a brief10 supporting Glaxo, would only say the organization is disappointed with the Supreme Court decision.

Earlier this year, the FTC issued a report11 noting that drug makers entered into fewer pay-to-delay deals, in general, in fiscal year 2014, following the 2012 Supreme Court ruling. The agency found that the total number of such deals dropped to 21 in fiscal year 2014 from 29 in fiscal year 2013 and 40 in fiscal year 2012 prior to the ruling.

[UPDATE: Sanford Bernstein analyst Ronny Gal wrote investors that a “critical question is whether this decision will open all the existing settlements in the industry which include a no- authorized generic” provision, which he noted is reasonably

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common. “This could wreak havoc on predictability of generic revenue for the next few years.”

While the risk may be higher, he pointed out that no-authorized generic agreements “are not necessarily illegal. The plaintiff (such as payers, FTC) still has to prove an antitrust case, which isn’t necessarily easy.” He also noted the refusal to hear the case is “not the same as agreeing with the Third Circuit… and until other appeals courts agree or a case is heard by the Supreme Court, “Third Circuit decisions only control outcomes in this circuit, not nationwide.”]

About the Author

Ed Silverman1

Pharmalot Columnist, Senior Writer

Ed covers the pharmaceutical industry.

[email protected] 12

@Pharmalot 2

Links 1. https://www.statnews.com/staff/ed-silverman/ 2. https://twitter.com/Pharmalot 3. https://www.parsintl.com/publication/stat/ 4. http://www.scotusblog.com/wp-content/uploads/2016/06/15-1055-Petition-for-

Certiorari.pdf 5. http://freepdfhosting.com/86224614d2.pdf 6. https://www.supremecourt.gov/opinions/12pdf/12-416_m5n0.pdf 7. http://www.scotusblog.com/wp-content/uploads/2016/10/15-1055-US-Amicus.pdf 8. https://www.statnews.com/2016/09/29/drug-companies-monopoly-podcast/

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9. https://www.statnews.com/pharmalot/2016/04/20/glaxo-generics-antitrust-gsk/ 10. http://www.scotusblog.com/wp-content/uploads/2016/06/15-1055-PHRMA-Amici-

Brief.pdf 11. https://www.ftc.gov/reports/agreements-filled-federal-trade-commission-under-

medicare-prescription-drug-improvement-0 12. https://www.statnews.com/pharmalot/2016/11/07/supreme-court-pay-delay-

glaxo-teva/mailto:[email protected] 13. https://www.statnews.com/topic/antitrust/ 14. https://www.statnews.com/topic/glaxosmithkline/ 15. https://www.statnews.com/topic/teva-pharmaceutical/

COMMENTARY

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 15 | AUGUST 1, 2018 1145

Ethical dimensions of the prescription opioid abuse crisis

Am J Health-Syst Pharm. 2018; 75:1145- 50

Timothy P. Stratton, Ph.D., BCPS, FAPhA, Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota College of Pharmacy, Duluth, MN.

Laura Palombi, Pharm.D., M.P.H., M.A.T., AE-C, Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota College of Pharmacy, Duluth, MN, and Carlton County Public Health & Human Services, Cloquet, MN.

Heather Blue, Pharm.D., BCPS, BCGP, Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota College of Pharmacy, Duluth, MN, and Emergency Department, St. Luke’s Hospital, Duluth, MN.

Mark E. Schneiderhan, Pharm.D., BCPP, Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota College of Pharmacy, Duluth, MN, and Human Development Center, Duluth, MN.

Address correspondence to Dr. Stratton ([email protected]).

Keywords: ethics, opioid, pain management

Copyright © 2018, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/18/0801-1145.

DOI 10.2146/ajhp170704

The number of deaths by drug over-dose in the United States tripled between 1999 and 2014 and reached a historic peak in 2015.1 Opioids were involved in nearly two thirds of these deaths despite few rigorous examina- tions of the benefits of opioid treat- ment for pain lasting greater than 3 months.1,2 Economic downturns and rural health disparities have been as- sociated with the increase in opioid overdoses.3-8 However, other consider- ations from an ethics standpoint have also contributed to the current opioid crisis.

Ethics is the study of right and wrong behaviors.9 An ethical dilemma arises when a difficult choice between competing moral needs must be made.10 This commentary will address some of the ethical considerations related to the current prescription opioid abuse crisis11 and the ethical dilemma of adequately addressing a patient’s chronic noncancer pain without possibly setting the stage for addiction to opioid medications.

Influencing prescribers. Many prescribers are undereducated regard- ing the appropriate use of opioids for treating pain.12 Prior to 1980, opioids were primarily prescribed by surgeons to treat immediate postoperative pain or prescribed for treatment of cancer-related pain.13 However, during the 1980s pain management “thought leader” Russell Portenoy, M.D., began presenting seminars promoting an in- creased role for opioid pain relievers in treating chronic noncancer pain, ar- guing that no dose of opioids was too high.14 Portenoy cited a 1980 letter to the editor of the New England Journal of Medicine that noted that less than 1% of patients treated with opioids became addicted.15 Portenoy also cit- ed his own retrospective review of 38 cases in which patients’ chronic non- cancer pain was treated with opioids, arguing that this case series provided evidence that opioids were effective for treating chronic pain.16 However, during this time Portenoy had finan- cial ties to more than 12 pharmaceu- tical manufacturers, including those producing opioid pain relievers. These relationships were not disclosed during Portenoy’s presentations.14

The American Pain Foundation was founded in 1997 as an indepen- dent nonprofit group advocating for the needs of patients who suffered from chronic pain. In 2010, however, the foundation reported that 90% of its $5-million annual budget was received

from pharmaceutical and medical de- vice companies; a single manufacturer of opioid medications provided 53% of the foundation’s funding.17,18 In 2001 the foundation supported attempts to block a class-action lawsuit filed by Ohio patients who claimed to have be- come addicted to oxycodone against a pharmaceutical company that was a long-term funder of the founda- tion.19 Further, in 2010 the foundation claimed that pain remained widely undertreated despite a 400% increase in the volume of pain medication pre- scribed since 1999.18

On May 3, 2012, the Ameri- can Pain Foundation website an- nounced that the foundation was being dissolved.18 (The nonprofit public interest–oriented news organi- zation ProPublica has archived many foundation-related documents online at www.propublica.org/series/dollars- for-docs.) Five days after the closure of the foundation, the U.S. Senate an- nounced that it was investigating man- ufacturers of opioid pain medications and pain treatment advocacy groups for possibly “promoting misleading in- formation about the drugs’ safety and effectiveness.” The Senate Finance Committee sent investigatory letters to 3 pharmaceutical manufacturers, 5 pain treatment advocacy groups (in- cluding the American Pain Founda- tion), the Federation of State Medical Boards, and the Joint Commission.

Moral failures contributing to the opioid abuse crisis included viola- tions of veracity (truth telling) and professional fiduciary responsibility, as well as failure to adequately man- age potential conflicts of interest.20 In a patient–provider relationship, fidu- ciary responsibility arises when the healthcare provider is trusted to act in the best interests of the patient and to not withhold information that might help the patient make an informed decision regarding treatment.21,22 Con-

COMMENTARY OPIOID ABUSE CRISIS

1146 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 15 | AUGUST 1, 2018

flict of interest arises when these 2 ethical principles are violated.

Influencing health systems. In 2000 the Joint Commission introduced its pain management standards.23 Ac- credited patient care facilities were compelled to systematically assess patients’ pain using “quantitative” measures first recommended in 1987 by the Institute of Medicine (since renamed the National Academy of Medicine).24 The Joint Commission’s updated 2001 standards first men- tioned pain as a “fifth vital sign” to be assessed in every patient.23 These new pain standards were justified in part by a study showing that, compared with patient-reported pain scores, pain intensity ratings by emergency department (ED) nurses “underesti- mated” pain on a 10-point scale (the mean patient and nurse ratings were 7.7 and 4.2, respectively).25

A pharmaceutical manufacturer funded educational sessions across the country, explaining the Joint Com- mission’s new standards.26 The Joint Commission agreed to allow only that company to distribute certain educa- tion videos and a pain management book, even allowing these materials to be purchased through the Joint Commission’s website. Over this same time period, a hospital study reported increases in opioid-related overse- dation, which rose from 11.0 to 24.5

Table 1. Evolution of Pain Management Standards of the Joint Commission23

Year How Pain Addressed in Standards

2001 Standards say, “Pain is considered a fifth vital sign”

2002 Standards say, “Pain used to be considered the fifth vital sign”

2004 References to pain as “fifth vital sign” deleted from standards

2009 Requirement that pain be assessed in all patients eliminated from standards

2011 Standards emphasize role of both drug and nondrug strategies in managing pain

2016 Standards recommend more-global assessment of pain and state that greater monitoring of opioid prescribing patterns within health systems is required

After 2016 Standards promote access to nondrug treatment modalities (e.g., acupuncture) and state that facilities are expected to use prescription drug monitoring programs

cases per 100,000 inpatient-days from 1997 to 2002.23 Subsequently, the Joint Commission began to walk back its pain management standards (Table 1).

Another nongovernmental organ- ization and several federal agencies also influenced opioid prescribing at the institutional level. The Federa- tion of State Medical Boards urged its member state boards to punish physi- cians who undertreated pain, promis- ing physicians immunity against pros- ecution for prescribing large amounts of opioids for the treatment of pain.26 It was discovered that since 1997, the Federation of State Medical Boards had received $2 million from pharma- ceutical manufacturers to support the federation’s educational efforts.

After closed-door meetings with the Food and Drug Administration (FDA) in the late 1990s, pharmaceuti- cal companies were permitted to use “enriched enrollment” in clinical trial design.26 This research approach in- volves initially assessing the efficacy of a study drug—such as an opioid— in an open-label phase in a group of patients.27 Nonresponders, as well as responders who suffer intolerable ad- verse effects, are then removed from the study population. The remaining responders are subsequently random- ly assigned to receive either the study drug or a placebo. As a result of en- riched enrollment, the efficacy of the

study drug relative to the placebo can be overstated: Patients who would not have responded to the opioid or who could not have tolerated the opioid’s adverse effects are not allowed to par- ticipate in the active treatment group, reducing the chances of treatment failure.26

The Drug Enforcement Adminis- tration (DEA) and the Department of Justice also played roles in this saga.28 DEA launched its “Distributor Initia- tive” in 2005, attempting to reduce the volume of prescription opioid med- ications finding their way into the il- legal drug trade by targeting manufac- turers, wholesalers, pharmacies, and prescribers. In 2011 DEA filed 131 civil cases against targeted entities and 65 “immediate suspension” orders against wholesalers. However, in 2012 an attorney new to DEA increased the burden of proof required by the DEA Diversion Office, subsequently slow- ing enforcement. By 2014 the number of DEA civil cases filed had dropped to 40, and the number of immedi- ate suspension orders had dropped to 9. These changes to DEA enforce- ment procedures were examined in a joint 60 Minutes and Washington Post investigative report that aired on October 15, 2017.29,30

An ethics analysis reveals that the Joint Commission, the Federation of State Medical Boards, FDA, and DEA all failed to adequately manage po- tential conflicts of interest, leading to a violation of fidelity, or the public’s trust that these nongovernmental and governmental agencies would prac- tice beneficence—to do good—in the interest of protecting public safety.

Influence of patient satisfac- tion surveys. The Centers for Medi- care and Medicaid Services (CMS) introduced its Star Ratings system in 2007 to allow Medicare patients to assess and compare the quality of care provided by physicians, hos- pitals, and other providers through the use of CMS’s Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. CMS tied Star Ratings to healthcare provid-

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er payments to incentivize providers to improve outcomes. Clinical qual- ity and customer satisfaction were among the metrics assessed,31 with the HCAHPS instrument including 3 questions specifically addressing pain management.32

Unfortunately, using Star Ratings to assess the quality of pain manage- ment had unintended consequences: Prescribers at facilities receiving low pain management scores increased their prescribing of opioid medi- cations.33 In at least 1 instance, a low-scoring hospital was reported to have offered “goody bags” containing opioid pain relievers to patients dis- charged from the hospital’s emergency department. In response to concerns over such practices, in November 2016 CMS announced the removal of the pain management questions from the HCAHPS survey.34

A number of ethics principles grounded in noble intentions led to unintended negative consequences. In CMS’s desire to remain faithful to its mission to optimize patient care (i.e., to practice fidelity), it modified the HCAHPS survey in an attempt to increase patient empowerment and participation in clinical decisions and address disparities in patient perceptions about the quality of care received (i.e., to achieve justice and equality). Unfortunately, CMS’s good intentions were derailed by unintend- ed consequences, leading to a failure of the precept of nonmaleficence (i.e., not doing harm).

Illustrative cases. Three of the authors of this commentary practice at clinical sites where patients are regularly affected by the opioid crisis. Below, each of the 3 has contributed a brief case study followed by a discus- sion of the ethical, legal, clinical, and social considerations arising from the use of opioids.

Case 1: Early opioid refill, over- dose risk, and substance use disorder. A middle-aged man travels 40 miles from his rural town monthly to see a pain specialist, receiving opioid pre- scriptions for chronic lower back pain.

The patient’s oral opioids include mor- phine sulfate 160 mg every 12 hours and immediate-release oxycodone hydrochloride 30 mg every 4 hours, for a daily dose totaling 590 morphine equivalents. During a recent clinic vis- it by the patient, the clinic pharmacist called the prescriber, recommending a reduction in the total daily dose of opioids and provision of a naloxone prescription to the patient to be used in case of an overdose; the pharmacist also noted that the patient’s most re- cent urine drug screen was positive for opioids (prescribed) and for diazepam and fentanyl (not prescribed). Howev- er, the prescriber made no mention of these test results in his care notes.

The patient returns to the clinic 7 days early to fill his monthly prescrip- tions. The pharmacist leaves a voice message for the provider, expressing concern. The prescriber’s reception- ist returns the pharmacist’s call with instructions to “fill a week early this time, because the patient is getting an magnetic resonance imaging scan and a surgical consult.” The prescriber has the receptionist convey that “the pa- tient is on a much lower dose than he was when he came to me. Naltrexone is not an option, for fear of inducing a withdrawal seizure.” The pharma- cist disagrees with this clinical rec- ommendation, is unable to talk to the prescriber directly, and is faced with the decision of whether or not to fill the opioid prescription.

Case 2: Controlled substance prop- erty. An ambulance brings to the ED a 55-year-old man in respirato- ry distress after an apparent opioid overdose. The emergency medical technicians also bring along sever- al of the patient’s home prescription bottles, including bottles containing 2 strengths of long-acting oxycodone and 2 bottles of immediate-release oxycodone. Additionally, the patient takes a prescribed benzodiazepine and has a history of depression, with a previous suicide attempt. The pa- tient’s wife states that her husband has been disappointed with the degree of relief of his chronic back pain despite

another increase in his pain medi- cation doses 2 days earlier. The ED physician believes the man has inten- tionally overdosed and wants the ED pharmacist to dispose of the prescrip- tion medications; the nurse wants to give them to the wife to take home. The pharmacist needs to decide what to do with the medications against a backdrop of unclear opioid use: This overdose could be either intentional or unintentional (i.e., a consequence of the recent dose increases combined with use of a sedative medication).

Case 3: Overprescribing in a rural area. A rural hospital serves patients from a wide geographical area. The hospital pharmacist has received many reports of inappropriate pre- scribing of opioids and is keenly aware of the high opioid overdose rate in the area. A local psychologist on the county’s drug-court team informs the pharmacist that several physicians in a local group practice seem to be prescribing opioids “like candy,” issu- ing or renewing opioid prescriptions seemingly without question for any- one who presents to the clinic and reports having pain. The psychologist asks the pharmacist to try to work with these independent physicians regard- ing their opioid prescribing practices.

How can the pharmacist balance the interprofessional ethical, legal, and clinical concerns arising in this case?

Case analyses. Ethical consider- ations. Despite the different practice and ethical challenges present in each case, common ethics themes emerge. Each case highlights the tensions sur- rounding the ethical use of opioids, a critical juncture of pharmacy practice and public health concerns. The phar- macist in each case is forced to con- sider patient autonomy versus pro- vider paternalism and how conflicting ethical considerations affect patient care. Relationships between phar- macist and provider, pharmacist and patient, and patient and provider also figure prominently in each case—the importance of sensitivity in commu- nications being a recurring theme.22 The pharmacist’s ethical obligation to

COMMENTARY OPIOID ABUSE CRISIS

1148 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 15 | AUGUST 1, 2018

prevent harm to an individual patient and to a population of patients, along with the obligation to act if harm is oc- curring, also looms large in each case. As demonstrated in case 3, pharma- cists may find themselves serving as the moral liaison not only between the patient and the prescriber but also be- tween those parties and public health and law enforcement officials.

Legal considerations. Case 1 high- lights legal implications involving risks to both the pharmacist’s and the physician’s license. How does the pharmacist balance the ethical and legal implications of providing a ques- tionable controlled substance refill while avoiding harm to the patient? Pharmacists risk being found negli- gent should an opioid prescription filled “early” result in patient harm due to overdose.35 A practice site’s risk-management plan should include procedures for expedited discussion of disputed early-refill requests with the practice site’s legal representative, including discussion of potential eth- ical and legal considerations and pa- tient follow-up plans.

The main legal question in case 2 involves the patient’s right to keep a medication prescribed for him or her even if the medication caused the patient harm in the form of potential overdose. Additionally, what liability does the prescriber incur by continu- ing to prescribe high doses of opioids or by concurrently prescribing opioids and benzodiazepines—or if the pa- tient has a history of substance abuse? This case highlights the potential benefit of consulting with the prac- tice site’s risk-management or legal representative before deciding on the disposition of prescriptions brought to the ED from a patient’s home.

Clinical considerations. Clinical considerations in these cases are in- separable from ethical considerations: management of substance use dis- orders; the role of urine toxicology interpretation; concerns with use of high doses of opioids; appropriate dose management and adjustment; the potential for “undermanaging”

chronic pain; immediate harm re- duction (e.g., preventing withdrawal while reducing the risk of death from prescription opioid, fentanyl, or her- oin overdose, especially when those agents are used in combination with benzodiazepines); long-term harm reduction (e.g., the advisability of re- ferral for substance abuse treatment); and alternative pain management strategies. These cases also bring to light biases that both pharmacists and physicians can have during the care of patients who are already using opi- oids chronically, as well as the inaccu- rate assumptions that might be made about such patients.

These cases may spark discussion regarding a possible relationship be- tween tighter restrictions on opioid prescribing and dispensing and an observed increase in the use of heroin. Recent efforts to reduce the nonmed- ical use of prescription opioids have coincided with increased rates of her- oin use, with deaths associated with heroin quintupling between 2000 and 2014.12,36 Indeed, some studies have indicated that policies and practices implemented to address inappropri- ate prescribing are now partially re- sponsible for the increases in rates of heroin use and associated deaths.37,38 For example, Evans and colleagues39 identified a temporal relationship be- tween a sharp increase in deaths due to heroin overdose and the introduc- tion of an abuse-deterrent form of oxycodone, which led some oxyco- done users to substitute heroin as a less expensive alternative.

Social considerations. The rural settings of 2 of the cases highlight the role that geography might poten- tially play in opioid-related care and health disparities. If a pharmacist in a rural community refuses to fill a le- gitimate opioid prescription, a patient may need to travel as many as 100 miles to have the prescription filled. Also, working as a member of a rural healthcare team can present challeng- es different from those encountered in nonrural areas. Rural pharmacists may have greater influence on the care

that a patient receives,40,41 and rela- tionships among the pharmacist, pa- tient, and prescriber may go beyond professional relationships to include personal ties.

Summary and conclusion. The opioid abuse crisis facing U.S. soci- ety today did not occur overnight or even over the previous decade; rath- er, it is the result of a perfect storm of circumstances that has been brewing for at least the past 35 years. This cri- sis arose through a combination of inadequate management of conflicts of interest, morally questionable in- teractions between regulators and the entities being regulated, question- able policies by government agencies, and unintended consequences of well-meaning efforts to optimize pa- tient care. Efforts by a number of these moral agents to “put the prescription opioid genie back into the bottle” are currently afoot. Unfortunately, just as the current crisis did not occur over- night, neither will solutions resolve things overnight.

Pharmacists in many practice set- tings are confronted daily with the need to strike an ethically acceptable balance between appropriate treat- ment of a patient’s chronic pain and not unintentionally contributing to the development of opioid addiction. To rein in the current opioid abuse crisis, it is imperative that pharma- cists go that extra step to ensure that lines of communication between the pharmacist and both prescribers and patients are maintained and transpar- ent throughout the treatment process. Pharmacists, prescribers, and other members of the healthcare team must attend to the ethical dimensions of the opioid abuse crisis if solutions to this epidemic are to be found.

Acknowledgments The authors gratefully acknowledge the community members and practice sites that have contributed to ongoing work to find solutions to the opioid use epidemic.

Disclosures The authors have declared no potential conflicts of interest.

OPIOID ABUSE CRISIS COMMENTARY

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 15 | AUGUST 1, 2018 1149

Additional information This commentary is based on the authors’ presentation at the Joseph A. Oddis Eth- ics Colloquium sponsored by the ASHP Research and Education Foundation and held at the 2017 ASHP Summer Meetings and Exhibition, Minneapolis, MN, on June 4, 2017.

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33. Falkenberg K. Why rating your doctor is bad for your health ( January 21, 2013). www.forbes.com/sites/ kaifalkenberg/2013/01/02/why- rating-your-doctor-is-bad-for-your- health/#1bcdbd3133c5 (accessed 2017 Feb 23).

34. Centers for Medicare and Medicaid Services. CMS finalizes hospital outpatient prospective payment system changes to better support

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hospitals and physicians and improve patient care. www.cms.gov/ Newsroom/MediaReleaseDatabase/ Press-releases/2016-Press-releases- items/2016-11-01.html (accessed 2017 Jul 10).

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4/6/2021 Unregulated supplements send thousands to hospital yearly

https://www.statnews.com/2015/10/14/unregulated-supplements-send-thousands-to-hospital-each-year/ 1/5

A

Unregulated supplements send thousands to hospital each year

By Megan Thielking1 2 Oct. 14, 2015

The emergency room at Boston Medical. Essdras M Suarez/The Boston Globe

t least 23,000 emergency room visits in the United States each year can be traced to dietary supplements, according to the first major study of adverse outcomes from products often marketed as healthy and natural.

More than a quarter of all the ER visits involved young adults — and many of them were taking weight-loss supplements or herbal energy products, according to the study, published Wednesday in

4/6/2021 Unregulated supplements send thousands to hospital yearly

https://www.statnews.com/2015/10/14/unregulated-supplements-send-thousands-to-hospital-each-year/ 2/5

the New England Journal of Medicine4. More than 20 percent involved young children who took supplements without supervision.

Some of the complaints that drove people to the hospital include: cardiovascular symptoms, such as heart palpitations and chest pain; allergic reactions; choking; and difficulty swallowing because of the large size of some supplement pills. The study was conducted by researchers from the Centers for Disease Control and Prevention.

The huge — and hugely popular — dietary supplement industry is largely unregulated. Previous studies have identified dangerous levels of certain ingredients in some supplements, including a chemical similar to the stimulant amphetamine.

But this is the first study to look systematically at side effects. The researchers reviewed nearly a decade of ER visits, covering 2004 to 2013.

“This study is the most important research that’s been published on supplements in the last 20 years,” said Dr. Pieter Cohen, a physician at Harvard Medical School who studies dietary supplements and wasn’t involved in the research.

“Now that we have the data, it should be a game-changer,” Cohen said, calling on the Food and Drug Administration and Congress to step up regulation of dietary supplements. “The belief is that they’re entirely safe, but now the science says that they’re not.”

Dr. Andrew Geller of the CDC, who wrote the study, said it’s likely that the study significantly underestimates the number of adverse events caused by dietary supplements.

4/6/2021 Unregulated supplements send thousands to hospital yearly

https://www.statnews.com/2015/10/14/unregulated-supplements-send-thousands-to-hospital-each-year/ 3/5

The study didn’t track patient visits to military hospitals, doctor’s offices, or urgent care clinics. It didn’t look at adverse events tied to dietary supplements in beverage form, such as energy drinks and herbal teas. And it didn’t look at deaths.

The supplement industry dismissed the study as insignificant, noting that many consumer products can cause injuries.

“Things are going to happen,’’ said Duffy MacKay, who heads scientific and regulatory affairs at the Council for Responsible Nutrition, a trade association for the supplement industry.

The group estimates that 150 million people in the United States take supplements, including children’s vitamins.

MacKay said the industry takes consumer safety seriously and recommends that people consult their doctors and follow instructions on the supplement packages. He also noted that a 2006 law requires manufacturers to report adverse effects of supplement use to the FDA.

“Over this 10-year period, a lot has changed to make these products more safe,” he said.

Dietary supplements include vitamins, weight-loss aids, herbal supplements, and similar products. Unlike pharmaceutical companies, supplement makers are not allowed to claim that their products cure or treat a particular condition, but can make general claims that they promote health and nutrition.

They are sold in supermarkets, pharmacies, and specialty supplement stories without prescriptions.

4/6/2021 Unregulated supplements send thousands to hospital yearly

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The FDA, under the Dietary Supplement Health and Education Act of 1994, is barred from reviewing dietary supplements for safety before they hit the market. The agency can intervene only when supplements are flagged as possibly dangerous, but the FDA said even that step can be difficult.

“The agency faces the challenge of having limited resources to monitor the marketplace for potentially harmful dietary supplements,” said Lyndsay Meyer, the FDA’s dietary supplement representative.

The FDA’s hands-off approach extends to the packaging of dietary supplements. The study found that many of the injuries to young children occurred because they got their hands on pills that were not stored in childproof containers.

The study called for “innovative safety packaging and targeted education” to reduce the risk to children.

A bill pending on Beacon Hill would make Massachusetts the first state to ban the sale of dietary supplements marketed for weight loss and muscle-building to children under 18. The bill would also require retailers to move the products from open shelves to behind the counter.

It has been tough to study dangerous side effects of supplements in the past because many people don’t share their supplement regimens with medical professionals — and medical professionals don’t often think to ask, experts said.

As a result, it can be difficult for doctors to tie specific symptoms to a patient’s use of dietary supplements.

4/6/2021 Unregulated supplements send thousands to hospital yearly

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“People may not realize that dietary supplements can cause any adverse effects,” Geller said. “While some may have benefits, the risks aren’t the same from supplement to supplement,” he added.

About the Author

Megan Thielking1

News Editor

[email protected] 5

@meggophone 2

Links 1. https://www.statnews.com/staff/megan-thielking/ 2. https://twitter.com/meggophone 3. https://www.parsintl.com/publication/stat/ 4. https://www.statnews.com/2015/10/14/unregulated-supplements-send-

thousands-to-hospital-each-year/ 5. https://www.statnews.com/2015/10/14/unregulated-supplements-send-

thousands-to-hospital-each-year/mailto:[email protected] 6. https://www.statnews.com/topic/dietary-supplements/ 7. https://www.statnews.com/topic/emergency-rooms/

Science & Society

The ethics of global clinical trials In developing countries, participation in clinical trials is sometimes the only way to access medical treatment. What should be done to avoid exploitation of disadvantaged populations?

Katrin Weigmann

C linical research by academic institu-

tions and pharmaceutical companies

has followed the general trend of

globalization and has moved inexorably

towards low- and middle-income countries

(LMIC). This trend has raised various

concerns, including whether the research

being conducted is of value to public health

in these countries or whether economically

disadvantaged populations are being

exploited for the benefit of patients in rich

countries. Nevertheless, clinical trials and

the research and health care that accompany

them can directly benefit patients, in particu-

lar those who would otherwise have no or

only little access to health care services. It is

therefore a matter of striking a fine-tuned

balance between the economic and research

interests of pharmaceutical companies and

academia and the needs of patients in LMIC

to make sure that all sides benefit.

......................................................

“. . . clinical research also helps to build research and health care capacity and can improve local infrastructure and boost the economy” ......................................................

Clinical trials are a necessary step in drug

development and are conducted throughout

the world, both in developed and in develop-

ing countries. Trials themselves are thus

not per se immoral, and there are a variety

of reasons to conduct responsible clinical

trials in LMIC. Doing so, for example, is

often the only way to test drugs and

vaccines for diseases that predominantly

afflict people in these countries; trying to

test the safety and efficacy of a malaria

vaccine in Europe or North America would

be relatively futile given the lack of patients.

Beyond the obvious and direct public health

benefits—in terms of both new knowledge

and new treatments—clinical research also

helps to build research and health care

capacity and can improve local infrastructure

and boost the economy. In fact, many

developing countries have been actively

trying to attract clinical research for these

reasons.

From the perspective of those conducting

the trials, a major benefit of LMIC is that it

is easy to enrol patients who are willing to

participate, particularly if they are poor. For

many of these patients, clinical trials are

their only access to medical care. However,

it is precisely this unmet medical need that

poses a risk for exploitation. “You want to

make sure that you don’t take advantage of

deprivation and that you don’t see the world

as a convenient population of sick people

where you can go and get the data that you

need to make more robust health systems in

high income countries”, commented Alex

John London, Professor of Philosophy and

Director of The Center for Ethics and Policy

at Carnegie Mellon University in the USA.

Indeed, human subjects research in LMIC

has often been criticized for exporting the

risk of research to those who will, in the

end, not be able to afford the resulting medi-

cal products. Clinical trials can pose real

health risks to participants, as the safety and

side effects of the drugs or vaccines being

tested are not yet fully known.

T he history of clinical trials and their

subsequent globalization can be

traced back to the thalidomide

scandal in Germany in the early 1960s.

Many children were born with severe

deformations of their extremities; it subse-

quently became clear that thalidomide, a

sedative developed by the German company

Grünenthal, caused birth defects in babies

whose mothers had been taking the drug

during pregnancy. Public outrage over the

devastating effects of the drug and the fact

that it had not been sufficiently tested for

safety fuelled discussion within the US Food

and Drug Administration (FDA) and quickly

led to legislation to improve the safety test-

ing of new drugs. The so-called Kefauver-

Harris Amendments were passed to prevent

another thalidomide disaster and—although

not directly related to the drug scandal—

introduced the requirement for drug manu-

facturers to prove drug effectiveness in

addition to safety.

......................................................

“From the perspective of those conducting the trials, a major benefit of LMIC is that it is easy to enroll patients who are willing to participate, particularly if they are poor” ......................................................

As the standards for safety and efficacy

developed over the decades, so did research

ethics principles. Again, it was medical scan-

dals that spawned today’s human subjects

regulations in the USA, most notably the so-

called Tuskegee Syphilis study. In this infa-

mous experiment, conducted from 1932 to

1972, US physicians denied penicillin, a

known treatment for syphilis since the late

1940s, to a cohort of syphilis-infected Afri-

can American sharecroppers to study the

natural course of advanced syphilis. Outrage

over these practices led to the passage of the

Freelance journalist in Oldenburg, Germany. E-mail: [email protected] DOI 10.15252/embr.201540398 | Published online 7 April 2015

EMBO reports Vol 16 | No 5 | 2015 ª 2015 The Author566

National Research Act in 1974 and eventu-

ally to the Belmont report, which forms the

basis for any human subject research

conducted in the USA. As a result, the regu-

latory process for drug development and

testing in the USA has very high standards,

but at a price: the US Food and Drug Admin-

istration (FDA) has been regularly criticized

for being disproportionately strict and for

requesting too much data. Clinical trials

have thus become increasingly complex and

time-consuming in the USA, leading to what

has been termed “drug lag”: prior to the

Kefauver-Harris Amendments, an average of

40 new drugs were introduced each year,

whereas the number dropped to 16 there-

after.

T he FDA is in a difficult position: being

too strict ensures safety, but it slows

down the approval process and can

delay new drugs from benefiting patients. If

this affects drugs for life-threatening

diseases, delays can cost lives if there are no

other treatment options. By way of example,

during the early 1990s, activists in the US

lobbied the FDA to ease its rules and expe-

dite approval for the first generation of anti-

HIV drugs because so many AIDS/HIV

patients were dying each year. On the other

hand, not being strict enough can lead to

public health problems if unsafe drugs enter

the market. Prominent examples are Rezulin

(troglitazone) and Vioxx (rofecoxib), both of

which turned out to have unacceptable side

effects.

......................................................

“Research began to leave the USA, first to Scandinavia and the UK, then to Eastern Europe and Latin America, and now to China and India” ......................................................

Yet, the FDA has an incentive to err on

the side of caution: lives lost owing to drug

delays usually results in fewer negative

headlines than lives lost to dangerous drugs

approved too soon. In addition, some of the

FDA’s regulations make clinical research

more burdensome and costly even without

improving human subjects protection or

drug safety. It has been argued, for example,

that requiring continued annual review by

Institutional Review Boards (IRBs) even for

minimal risk studies is simply not necessary.

In addition, multicentre studies are often

reviewed by multiple local IRBs, a costly but

redundant procedure. When clinical trials

started to move abroad in the 1980s, strin-

gent FDA regulations were a major factor,

and still are today.

FDA regulation is not the only reason

that so many clinical trials have moved to

LMIC [1]. Because many new drugs confer

only a small benefit over existing treat-

ments, ever larger trials with increasing

numbers of human subjects are required to

measure improvements with statistical

significance. This has become particularly

relevant for so-called me-too drugs that are

chemically very similar to those already on

the market. Recruiting a sufficient number

of patients therefore remains a major bottle-

neck for medical research, and companies

have turned to LMIC to conduct trials

because it is easier to find participants there.

Moreover, operational costs in developing

countries are low and there are large pools

of “treatment-naive” patients, whereas in

traditional research areas, the use of too

much medication generates the risk of drug–

drug interactions. Research began to leave

the USA, first to Scandinavia and the UK,

then to Eastern Europe and Latin America,

and now to China and India (Fig 1). A recent

investigation found that the 20 largest US-

based pharmaceutical companies were

conducting one-third of their clinical trials

solely at foreign sites, while the majority of

study sites are outside the USA [2].

W hen research by US companies is

carried out in other countries,

the FDA still has some responsi-

bilities to ensure that these comply with

ethical standards. But there are doubts

whether all the US rules and regulations

should be exported to other countries. “The

US regulatory system is far from perfect, it

has been criticized as being overworked and

inefficient. Some would argue that it is not

the best model to bring to lower income

countries that don’t have the resources we

have”, said Sandra Alfano, Research Scien-

tist at Yale School of Medicine and Chair of

Yale’s Institutional Review Board (IRB).

Moreover, not all ethical principles have

cross-cultural validity. Informed consent, for

example, is a central concept for any

research with human subjects. However, as

Alfano remarked, “the principle of informed

consent flows out of a Western philosophy

of individual autonomy. That does not

always translate well to other countries”. An

Eastern philosophy, she explained, may

rather rely on community or family decision.

“Individualism is not a universally embraced

idea”, she said. She therefore thinks that

Western researchers “should be strongly

encouraged to involve the local community

in setting the agenda—deciding whether this

is a good project to be done—and then help-

ing to design the research protocol and

addressing the question about who is the

right body to give consent”. This principle is

referred to as “community-based participa-

tory research”, or CBPR. “CBPR is really the

focus on everyone’s mind, but it is very diffi-

cult to achieve”, Alfano said.

......................................................

“. . . the primary goal of conducting clinical trials in developing countries should be to address the health needs of the host population” ......................................................

Despite cultural differences and the

need to collaborate with local communi-

ties, there are guidelines for conducting

research in international settings, notably

the Declaration of Helsinki (DoH) by the

World Medical Association (WMA), and

the international guidelines for biomedical

research involving human subjects by the

International Organisation for Medical

Sciences (CIOMS). They are not legally

binding, but set out important standards

nonetheless. “Many countries refer to the

DoH in their legislation. But what is more

important is that it is a document written

by physicians and for physicians. There is

a moral obligation for physicians to stick

to these rules”, said Ramin Parsa-Parsi,

Head of the Department for International

Affairs of the German Medical Association.

The DoH was adopted in 1964 and has

since undergone seven revisions, most

recently in October 2013. A major revision

was made in 2000 in response to studies

performed with US federal funds of mother–

child transmission of HIV in developing

countries, which denied effective medication

to participants in the placebo control arm.

The DoH, in its 2000 revision, accordingly

greatly limited the use of placebos. However,

some argued that this would restrict research

too much and that long-term benefits would

justify the use of placebos [3]. The FDA,

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Katrin Weigmann Clinical trials in developing countries EMBO reports

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when regulating studies outside the USA,

kept referring to older versions of the DoH

and, in 2008, abandoned referring to it

altogether at the expense of the “Harmoni-

sation of Technical Requirements for Regis-

tration of Pharmaceuticals for Human Use

Good Clinical Practice” (ICH-GCP) guide-

lines. “The ICH-GCP has been created by

European, Japanese and US regulators in

collaboration with the pharmaceutical

industry. There are large differences in

ethical standards between the DoH and

ICH-GCP, particularly in the areas of

placebo use and post-trial access”, Parsa-

Parsi explained.

The newest revision of the DoH, issued

in late 2013, leaves the placebo paragraph

essentially unchanged. The ICH-GCP regula-

tion, on the other hand, is much more

permissive: it explicitly states that the stan-

dard of care required to be provided to the

control group depends on the population,

meaning that control group subjects are only

entitled to the standard of care they would

otherwise receive locally. This is morally

ambiguous. According to London, “you

can’t use the mere fact that people don’t

have access to an intervention that works to

say that you don’t have an obligation to

provide them with something that works”.

T he ongoing debate shows just how

difficult it is to define ethical stan-

dards for research in international

settings, to walk the narrow line between

protecting research subjects and enabling

research that contributes to the social good.

According to London, the question of

placebo-controlled trials should be viewed in

the context of the research question studied.

In his view, the primary goal of conducting

clinical trials in developing countries should

be to address the health needs of the host

population. “In general, we should provide a

high standard of care”, he said, but main-

tained that there could be rare exceptions.

Such exceptions might be in cases where

placebo-controlled trials are particularly

important to developing countries: for exam-

ple, when testing a new intervention that is

similar to but cheaper than existing drugs, or

one that has some other characteristic that

conveys particular advantages in LMIC. One

such feature would be heat resistance, which

would make it easier to transport medication

to remote locations in tropical areas. In such

cases, it would be reasonable to use a

placebo control in the trial, as it will be

difficult to compare the efficiency of the new

product to the existing one.

A crucial aspect in the DoH and CIOMS

guidelines concerns research on vulnerable

groups. If people in developing countries

belong to severely socio-economically disad-

vantaged populations, this would impact on

their freedom to consent, making them

susceptible to undue influence and there-

fore vulnerable. According to the DoH,

research in vulnerable groups is only justi-

fied, “if the research is responsive to the

health needs or priorities of this group and

the research cannot be carried out in a

Source: http://ClinicalTrials.gov

MEXICO

2309 AFRICA 4375

CENTRAL

AMERICA

2163

EAST ASIA

17010

EUROPE

51990

MIDDLE

EAST

7775

NORTH ASIA

3463

PACIFICA

4914

SOUTH

AMERICA

6334

SOUTH

ASIA

3097

SOUTHEAST ASIA

3835

JAPAN

3589

UNITED

STATES

83689

CANADA

13555

LEAST MOST

Colours indicate number of studies in clinical trials with locations in that region

Labels give exact study count

Figure 1. Distribution of study locations of all trials registered with ClinicalTrials.gov.

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EMBO reports Clinical trials in developing countries Katrin Weigmann

568

non-vulnerable group. In addition, this

group should stand to benefit from the

knowledge, practices or interventions that

result from the research”.

......................................................

“. . . taking advantage of people’s deprivation to impose on them the risk of health research can be exploitive if it is not carefully planned and regulated” ......................................................

“We have discussed including, in addition

to the current requirements which reflect

the ‘reasonable availability’ approach, a

wording on fair benefits”, Parsa-Parsi said.

Indeed, “fair benefits” is a hotly debated

topic. Whereas the DoH and CIOMS base

ethical acceptability mainly on responsive-

ness to health needs of the host commu-

nity, others maintain that research is

justified as long as the host community

receives “fair benefits” in a more broadly

defined sense. Such benefits would not

have to be directly related to the research

projects and might include employment and

training for community members or the

building of infrastructure [4]. However,

after long debates and consultations with

developing countries, a fair benefits option

was not included in the current version of

the DoH. “The possibility of exploitation—

that you buy consent with money or other

benefits—was considered too high by the

WMA”, Parsa-Parsi explained. London takes

a similar view: “Ancillary benefits are

important, but I don’t think they can make

up for lack of relevance of the science to

local health needs”, he said. For him,

addressing the local health needs is the key

issue. But ethical commitment should not

stop there. “Just because I know the answer

doesn’t make you better off. That informa-

tion then has to be translated into some-

thing from which you benefit concretely”,

he said. “You start by studying the health

needs, you build up an information base

needed to discover interventions that work

and then you close the cycle of translation

by making those interventions and that

knowledge available to their communities.”

Availability of the drugs developed

remains another major issue. Medication is

often far too costly people in LMIC to afford,

but with time, that too can change. “People

were worried that HIV studies carried out in

LMIC were not relevant to local health needs

because the drugs were too expensive”,

London recalled. “Ten years later, many

more people have access than what was

originally expected.” According to the WHO,

the number of patients taking antiretroviral

therapy has increased rapidly in LMIC since

2003 from just 400,000 to 11.7 million by

the end of 2013 (http://www.who.int/gho/

hiv/epidemic_response/ART_text/en/).

I n the meantime, other diseases are taking a

terrible toll in LMIC, and it is not clear

when new drugs will be cheap enough for

wide use by their citizens. Hepatitis C, an

infectious disease that can lead to liver cirrho-

sis, is on the rise globally, and developing

countries carry the highest burden with infec-

tion rates as high as 11% in Egypt, 4.8% in

Pakistan and 3.2% in China. During the past

decade, research has led to the development of

new drugs that work more effectively, in less

time and with fewer side effects. Moreover, in

contrast to the previous treatment regimens,

these all-oral medications do not require regu-

lar interferon injections, making them ideal for

use in remote settings. The drugs are just start-

ing to come to market, with more in the pipe-

line, but their cost at the outset puts them out

of reach for most people in developing coun-

tries. It is likely that, as in the case of AIDS

medication, it will take long until they become

available to most LMIC.

In many cases, therefore, studying local

health needs will not necessarily generate

immediate benefits for poorer communities.

Nonetheless, studies that are responsive to

local health needs will generate information

that is necessary to improve public health in

the long run. “When you ensure that the

information is relevant to the local popula-

tion, you build the foundation of knowledge

necessary to generate beneficial interven-

tions and policies, and this is a kind of bene-

fit itself”, London commented. Making

important new treatments available in LMIC

should be considered a health priority, but

this might take years or even decades at the

current rate of progress. For participants in

clinical trials, it will therefore be important

to help them to bridge the gap between the

end of the trial and the time the drug

becomes available in their country.

B oth the CIOMS and the DoH require

studies on vulnerable groups to

address their health needs. But does

research in LMIC address local health needs

in reality? According to the 2014 report by

the Access to Medicine Foundation, an inter-

national not-for-profit organization that

ranks the top 20 research-based pharmaceu-

tical companies with respect to their efforts

to improve global access to medicine

(http://www.accesstomedicineindex.org/),

there is some promising development, but

there is still a long way to go. “There is

evidence of sustained commitment to R&D

for relevant diseases, with most companies

having an R&D strategy in place that explic-

itly takes patients in developing countries

into account”, the report says. More

precisely, the index investigated research

activities on 47 diseases that were regarded

as most relevant to LMIC according to the

WHO. Although a number of studies tackle

these diseases, the research activities can

mainly be attributed to only five of the 20

companies, and they concentrate on only

five of the 47 diseases: diabetes, lower respi-

ratory infections, hepatitis, HIV/AIDS and

malaria. Neglected tropical diseases, as the

report shows, remain neglected. In addition,

the report criticises companies’ lack of effort

to make their products available to people in

LMIC: “On average, products are registered

in only [. . .] 8% of low-income countries

covered by the Index.”

Conducting clinical trials in LMIC is not

intrinsically immoral. Indeed, trials some-

times represent the only medical treatment

that patients in deprived settings can hope

to receive, and can also provide other

advantages at the personal, community and

national levels. Nonetheless, taking advan-

tage of people’s deprivation to impose on

them the risk of health research can be

exploitive if it is not carefully planned and

regulated. At the moment, there is such a

variety of legislation that the conduct of

trials differs widely, often depending on why

a company decided to use a developing

country in the first place. Trials that address

locally relevant diseases and that will deliver

affordable drugs and care for the local popu-

lation are certainly to be lauded. Ones that

do not provide immediate or obvious bene-

fits locally are less laudable and must be

assessed on a case-by-case basis.

References 1. Petryna A (2009) When Experiments Travel:

Clinical Trials and the Global Search for Human

Subjects. Princeton, NJ: Princeton University

Press

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2. Glickman SW, McHutchison JG, Peterson ED,

Cairns CB, Harrington RA, Califf RM, Schulman

KA (2009) Ethical and scientific implications of

the globalization of clinical research. N Engl J

Med 360: 816 – 823

3. Wolinsky H (2006) The battle of Helsinki:

two troublesome paragraphs in the Declara-

tion of Helsinki are causing a furore over

medical research ethics. EMBO Rep 7:

670 – 672

4. Schulz-Baldes A1, Vayena E, Biller-Andorno N

(2007) Sharing benefits in international health

research. Research-capacity building as an

example of an indirect collective benefit.

EMBO Rep 8: 8 – 13

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