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European Pharmaceutical Contractor

Patient Protection

There have been copious writings on the protection of vulnerable test subjects, and with good reason. In the murky past of medical research, much was done to humans in the interests of science that investigators would never consider today. But even though there is little debate as to the regulatory, ethical and legal definitions of vulnerable patients, the subject is still a vital one, as new and troublesome issues – such as the globalisation of clinical trials, and increasingly easy access to the internet and social media – have complicated privacy and safety.

In the strictest of terms, vulnerable populations are any for whom special protections should be afforded: groups or individuals who are unable to make fully-informed decisions on their own, or those who are susceptible to coercion. Thus, patients with cognitive or communicative dysfunction, and/or those unable to assess or understand the implications of their decisions – children, for example – would be ineligible or require extra protection.

Other vulnerable classes may include persons who are institutionalised, terminally ill, economically dependent or impoverished, as well as certain social minorities. Vulnerability is not necessarily limited to a chronic situation or entire population; it can be induced whenever there is an unequal perception of power, created by a need for services, assistance or protection, or caused by cultural, ethnic or religious beliefs.

A History of Abuse

History has seen a litany of abuses to the rights of patients, and particularly to those in vulnerable populations. However, many of the significant changes in regulatory and statutory guidance for the ethical study of medicine have come from those same atrocities. Going back to the 1940s, test subjects were often prisoners or individuals in mental institutions who were often not fully competent, informed of the study’s risks or asked for consent.

One of the earliest attempts to codify ethical research practices was the Nuremberg Code, developed in 1949 in response to the medical experiments described in the Doctors’ Trial of Nazi researchers at the end of the Second World War. It outlined 10 principles for ethical research, beginning with the importance of voluntary consent from research subjects (1).

Sometimes, the medical goals of investigators cause them to focus on the ends, rather than the means, of research. When the US government was desperate to find a solution to the devastating toll of sexually transmitted diseases on American armed forces during the 1940s, researchers intentionally infected subjects with the disease-causing pathogens, deliberately causing debilitating illnesses. The preferred subjects were prisoners in federal correctional institutions, because they could be easily monitored and controlled.

Two notorious studies were overseen by Dr John Charles Cutler, Acting Chief of the venereal disease programme at the US Public Health Service: infection of prisoners with gonorrhea at the US Penitentiary at Terre Haute in 1943, and with syphilis at Sing Sing Correctional Facility in 1953. Cutler was named Assistant Surgeon General in 1958, but was also later tied to the infamous Tuskegee syphilis experiment – during which, several hundred African-American men who had contracted syphilis were observed, but left untreated (2).

Evolving From Mistakes

In response to the abuse committed in the Tuskegee study, the US Congress passed the National Research Act in 1974, which established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. This commission drafted a set of guidelines called the Belmont Report, aimed at securing the ethical conduct of research, and including three key principles: respect for persons, beneficence and justice.

Ethical standards for human research have continued to evolve from regulatory agencies such as the FDA, as well as from bodies like the Council for International Organizations of Medical Sciences and the WHO. The WHO’s Declaration of Helsinki states: “In research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject.” It continues: “In any medical study, every patient – including those of a control group, if any – should be assured of the best proven diagnostic and therapeutic method.”

New Patient Safeguards

Nearly 75 years have passed since these first medical research injustices, and the world has become a more complex place to live, practice medicine and, certainly, develop drugs. Just as past mistakes have been learned from, to improve the protection of patients, the industry will have to evolve to meet the challenges of the future.

To aggressively guard against widespread abuses of power – such as data falsification, collusion or the introduction of bias (intended or otherwise) – pharma has implemented a robust system of checks and balances to help ensure patient safety, including:
  • Institutional review board (IRB), or ethics committee (EC) and data safety monitoring board reviews
  • Financial disclosure by investigators
  • Data quality control
  • A comprehensive informed consent process, designed to ensure trial participants fully understand the potential risks and benefits of the research
While these safeguards are in place to guarantee that patient safety is respected in all clinical trials, they are especially vital to vulnerable populations.

Global Protection

One potentially vulnerable population needing these kinds of safeguards is the growing number of participants in trials conducted outside the US. In a guidance titled FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND (investigational new drug), the agency noted that the increasing globalisation of clinical trials presents additional obstacles to patient safety – not least that it constrains the number of oversight inspections that are possible.

One would like to presume that in all countries, basic protections would be enacted in the form of regulatory law/guidance – with other statutory instruments that govern medical ethics in place – to preclude investigators from enrolling non-compliant patients or using monetary reward, coercion or deception to fill clinical studies. But, without robust oversight, it is impossible to adequately monitor the volume of trials taking place around the world.

However, FDA guidance stipulates that any foreign clinical studies that are not conducted under an IND should conform to the ethical standards of Good Clinical Practice in 21CFR 312, including independent review of the protocol by an EC/IRB. Furthermore, such studies should be compliant with ICH E6, which defi nes the informed consent process as when “a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate”.

Quoting Sidney Wolfe – Director of the Public Citizen’s Health Research Group – on a 2014 Health and Human Services report on FDA inspections of sites outside the US, Psychiatric News said: “The quality of the data used by the FDA as a basis for approving the drugs being studied may well be flawed, resulting in dangerous, incorrect decisions to approve drugs, jeopardising the health of people in this country and elsewhere. Massive marketed use of drugs that possibly should not have been approved extends the dangers beyond the subjects of the clinical trials to the general public” (3).

Without sufficient oversight, the FDA cannot know exactly how studies are conducted outside the US, any more than it can miraculously create a budget for additional overseas inspectors. For the time being, the FDA is encouraging sponsors to utilise data standardisation, and is actively engaging in collaboration and outreach with international regulatory authorities. To protect data integrity, the agency is also considering alternative mechanisms of trial oversight – both by sponsors and itself – such as quality management systems that emphasise building excellence into the research process (4).

Social Media

Any individual seeking medical treatment is largely or completely dependent upon a medical professional and, typically, has neither the training nor expertise to challenge diagnosis or treatment options. This paradigm exists in many aspects of daily living, but in few areas with such personal consequences: you may be dependent upon your mechanic to accurately diagnose the needs of your vehicle, but you are unlikely to suffer harm to health or wellbeing if the mechanic is dishonest or wrong.

This dependency on medical professionals is both mitigated and further complicated by the instant availability of information via the internet. In the doctor’s office, there is the benefit of a learned intermediary to filter information. On the internet and social media, material – although potentially true and valuable – is unfiltered and left to the end-user to interpret.

Consider how this unregulated flow of information may affect potentially susceptible patient populations – like those who are overweight, hard of hearing or arthritic, who could fall victim to ‘miracle cures’ that may actually provide little or no benefit. Claims made by these marketers are not scientifically substantiated, nor subjected to the rigours of regulatory review. In the digital age, end-users are particularly vulnerable to the power of suggestion when they become desperate for a cure to a lingering medical issue.

At the Ethical Core

The FDA and other international regulatory bodies are tasked first and foremost with protecting the health and welfare of their populations. They have implemented safeguards to protect vulnerable classes, but cannot stop individuals from trying to circumvent these defences by buying unregulated treatments or therapies. Even within the confines of clinical development, where a substantial level of regulatory and ethical review is required, a broad spectrum of standard of care exists. This may be due to variability in international legislation, or social or economic pressures but, as a result of these inconsistencies, global trials can become challenging to harmonise. In some countries, where particular therapies may not be available, access to these drugs represents a significant treatment advantage. Some may see this as a win-win scenario, matching needy patients with their required therapy; others may see this as exploiting people who have limited options.

Despite the inconsistency that exists in medical research around the world, certain principles such as the Declaration of Helsinki and, indeed, the Hippocratic Oath, provide the core ethical framework needed to protect all patients from risk to their health, wellbeing and privacy. As investigators, medical monitors, regulators and clinical trial staff, we must approach patient safety as the number one priority of our work and remain vigilant in protecting all – from the very least to the most vulnerable.


1. Trials of war criminals before the Nuremberg military tribunals under control council law, Government Printing Office 10(2): pp181-182, 1949. Visit:
2. Pittsburgh Post-Gazette, John Charles Cutler obituary, 12 February 2003. Visit:
3. Daly R, Investigation finds little oversight of foreign clinical trial sites, Psychiatry News, 10 October 2014. Visit:
4. US Department of Health and Human Services – Food and Drug Administration Center for Drug Evaluation and Research, Guidance for Industry and FDA Staff, FDA: Acceptance of Foreign Clinical Studies Not Conducted Under an IND, March 2012. Visit:

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In addition to overseeing biopharmaceutical development, and strategy for drug and biologic development, Marc Hoffman is responsible for leading the clinical supply, medical, regulatory and pharmacovigilance operations of Theorem Clinical Research. A 25-year veteran in clinical research, he was Vice President of Medical and Scientifi c Affairs at Covance, and has served in a variety of clinical development, medical affairs and regulatory roles for organisations such as Hospira, Baxter Healthcare Corporation, Kendle and PAREXEL. Marc holds a BA in Psychology from Emory University, US; an MD from the American University of the Caribbean School of Medicine; and a diploma in Pharmaceutical Medicine from the Royal College of Medicine, UK.
Marc Hoffman
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