Ethical guidelines and the principals of good science in medical research have been a source of debate in forums and committees the world over since the end of the Second World War. Over the years, different guidelines and regulatory frameworks have been drafted in an attempt to balance the delicate issue of clinical trials and human subject protection. A general international framework for good clinical practice (GCP) was laid out for the first time as a unified standard – mutually accepted by the European Union, Japan and the United States – in the International Conference on Harmonization (ICH) GCP guidelines. Around the same time national GCP standards developed in countries around the world. Many hope these national values will mature into regional legal frameworks for regulating clinical research.

Francis P. Crawley[1], Director General of the European Good Clinical Practice Alliance in Brussels, Belgium, is concerned with shifting debate forward on the issue of internationalizing ethics in biomedical research. Not least among the list of his achievements is the World Health Organization (WHO) Operational Guidelines for Ethics Committees That Review Biomedical Research (subsequently referred to as the WHO guideline). This document, which was completed in 2000, developed out of an earlier guideline he wrote for European ethics committees. The WHO guideline has subsequently been adopted around the world as a blueprint establishing, in Crawley’s words, “an international standard for establishing consistency, developing thoroughness, and ensuring quality in ethical review.”

The WHO guideline has provided a point of consensus for ethical review while also promoting ethical reflection by all parties making up the biomedical research community. The impact of the guideline is evidenced by the number of translations in major languages, which is more than thirty in all.

“Most of the translations were done by people who really themselves took the initiative,” Crawley explains. This would seem to reinforce the view that almost everyone involved in biomedical research wants guidance on what and what not to do.

It is fair to say that a debate exists over the nature of the reason for providing ethical guidelines. On the one hand, there are the Kantian proponents of the view that legislation is undesirable because simply following a rule is not a moral action but an action of constraint; on the other hand, those opposed to this view say that rules are essential to guarantee and demonstrate that agents of research act properly and responsibly.

“I think we need legislation,” says Crawley, “I think we need laws not only to constrain people but in order to know what we can do in a framework that is acceptable to society.”

As he sees it, when dealing with the unknown, as in science, knowing the right course of action is inherently shrouded in uncertainty and knowing how to behave in this environment is equally difficult to ascertain. The act of investigating the unknown is often driven by strong moral desires: finding a new therapy for cancer to prevent suffering is clearly morally commendable. The research challenge arises in the mode of investigation: the risky use of individual human subjects to obtain a public good. For this reason, those involved in clinical trials require guidance to ensure not only full human subject protections, but also a certain area of comfort, morally and legally for themselves.

For Crawley, the medical research community’s ability to interpret ethics and understand the fundamentals of GCP is as important as clearly documented sets of procedures. “When we create legislation regarding research practices there is also a concomitant responsibility to educate, where people learn both to understand what the rules are, while also achieving a capacity to act according to what they understand is the right thing to do,” he says, “this understanding and capacity are both needed for good practice.”

Rather than dictating a set of laws to the biomedical research community Crawley’s goal is to assist researchers and sponsors “to consider the ethical issues involved in the research they are undertaking, and not simply allow these questions to be raised only by the ethics committee or regulatory authority.”

Crawley says the most important principle for researchers to consider is “respect for the dignity of persons.” From this single guiding principle, he says, all others – beneficence, non-malevolence, justice – are derived.

With reference to the recent criticism surrounding Pfizer’s clinical trials in Nigeria, where both company employees and government bureaucrats were condemned for allowing an unapproved drug to be tested on children, Crawley describes what he hopes guidelines can help achieve; namely a national framework that makes good research possible by truly protecting research subjects and allowing researchers to act correctly and confidently.

“We want to develop a national GCP guideline, and eventually I would like to see national legislation in Nigeria, because if there is clear legislation it will be clearer for researchers and their organizations to go in and address serious health issues because they will know what is expected from them and there will be systems to work inside of,” he says.

The goals seem simple enough, so why all the confusion? From an industry perspective complications arise when implementing the guidelines.

Neil Patel, currently a Director in the pharmaceutical research and development operations practice at PricewaterhouseCoopers Pharmaceutical and Life Sciences Advisory Services, recounts a tale of his experience opening the door for research in India with a global drug research company.

“One of the risks we articulated going into India was that we didn’t know what guidelines we should be following and how they would be enforced,” says Patel

Despite attempts at harmonization, ethical review remains a national activity that is increasingly influenced by international homogenization – a characteristic as unlikely to change as the nation state system, says Crawley. Why? Because ethical review is connected to biomedical research and biomedical research is intimately tied to the provision of healthcare which is funded by taxpayers and coordinated by national governments.

“No matter how internationalized or globalized the pharmaceutical industry, or the biomedical industry, or the manufacturing industry becomes; [pharmaceutical companies] will still have to sit down and negotiate in every country,” says Crawley.

Patel describes how the company he worked for addressed the issue by learning operationally through a Contract Research Organization (CRO) which was already based in India.

Increasingly, clinical trials are conducted outside the borders of the sponsoring country, an exercise in cost saving for the research organization but also suited to improving the health and bolstering the capacity of medical infrastructures in less developed communities. However, Patel warns that while these communities may have patients and trials may be cheaper to operate there, the sponsor organization should be aware of the quality of the investigators available to conduct the trial.

“The number one issue in clinical operations is recruitment, not just patient recruitment, but what is less well addressed, in my mind, is investigator recruitment,” he says. Patel explains that typically in an effort to increase patient enrollment companies will add more trial sites provided they meet the pre-study quality criteria of GCP.

“One thing companies should start considering is going more for quality and less for quantity,” says Patel, adding that building relationships with investigators is the best way to make sure they are truly capable of conducting clinical research in your name. “Take the time to really say, you know what, we can’t pick that site, it looks good on paper but they just don’t understand how to do clinical trials.”

The big issue in ethics inevitably comes down to the logistics of implementation. Patel explains that in designing the study protocol, an appreciation of logistical issues is the key to avoiding costs further down the road. No one wants to discover after the trial has started that implementing the protocol is not feasible. This is one reason for the increasing popularity of Electronic Data Capture (EDC) systems that are capable of exposing errors almost immediately. But these systems in turn come with their own challenges of implementation.

When it comes to GCP inspection agencies like the US Food and Drug Administration (FDA), themselves limited by a lack of resources, it’s possible to pick and choose the issues for inspection. More often than not the regulators choose topics that are already in the public eye, highlighted by media reports, whistleblowers or legal investigations.

Kate Maloney, also with PricewaterhouseCoopers Pharmaceutical and Life Sciences Advisory Services, is used to addressing the issues of compliance in GCP with her clients. Maloney offers a number of heightened points that she has noticed in recent GCP inspections by the FDA, the European Agency for the Evaluation of Medicinal Products (EMEA) and the Medicines and Healthcare products Regulatory Agency (MHRA). These include, but are not limited to: the use of qualified inspectors; consistency between the study protocol and informed consent agreements; confidentiality of patient information and trial data; the existence of effective quality assurance strategies; good archiving and record retention systems; and the handling of supply between sponsor and investigator.

“It’s not easy to capture everything,” says Maloney, “therefore taking a risk-based approach to GCP compliance oversight and management is important”.

Echoing the sentiments of her colleague, Maloney says “there are a number of times over the course of the years where regulators have sited investigators doing trials that they are not qualified to be doing.” She claims nowadays one of the key focuses of regulators during a GCP compliance inspection is looking at investigator and staff credentials, experience and training documentation. 

Informing subjects of the nature of a trial, including both the risks and potential benefits, is an integral part of the informed consent process. Providing subjects with enough information and time to consider participation in a trial has often been a stumbling block for clinical trial investigators but re-consenting subjects in a trial, based on protocol changes, is a bigger feat to complete.

“Informed consent updates have become a target in GCP compliance inspections,” says Maloney. “Subjects have to re-review and resign an informed consent if there are any changes to the protocol. This has become an issue because patients enrolled in a trial may be subjected to changes in the protocol that they have not consented to.”

Today as the scope of clinical trials is widened to accommodate the global market for healthcare products, the chances are slim that the first draft protocol will remain unchanged for the duration of the trial. The protocol is often reworked, thereby mandating that anyone involved in a trial is informed of the modification and the ensuing risks and benefits. This applies to any alteration no matter how small.

According to Crawley “it doesn’t matter what the risk is, or what the impact will be on the person; the moral criteria still remains: you want to use that person as a means for something, so they must agree to it.”

In order to minimize the risk of things going wrong in a trial, it’s important for sponsors to have a schedule in place for monitoring and auditing their clinical studies. Regulators look at the Quality Assurance (QA) plan and the results of sponsor audits during their inspections, according to Maloney, so it’s critical to have an annual QA plan and documented audit and follow-up information in place.

“It’s the responsibility of the sponsor organization to be monitoring and auditing their trial sites and vendors on a regular basis,” she says.

If, as a result of an audit or monitor report, the sponsor finds that there is a concern, an action plan to resolve the issue should be documented. Maloney says that regulators are scrutinizing sponsor Corrective and Preventive Action (CAPA) plans to see if they have been implemented, if they are being monitored, and what process is in place to determine if they are effective in correcting the problem.

Maloney says as part of GCP compliance, companies must have appropriate record management and archiving plans. Many see EDC as an attractive option to simplify data collection and management. However, due to the direct transfer of information to the sponsor, the investigator is cut out of the equation, contrary to GCP  which states that the investigator must retain source documents at the trial site for a period of time stated in the regulations.

Additional concerns highlighted by recent GCP inspections include training controls, which historically have been one of the top 10 problem areas that cause FDA Form 483 citations along with supply and handling of investigational products. Maloney says, “the sponsor is responsible for maintaining Investigational Medicinal Product (IMP) batch and distribution records that go out to the investigators, and it’s the investigators responsibility to confirm batch delivery, manage and document dispensation and the return or destruction of all unused IMP at the end of the trial. Sometimes there is a discrepancy that can't be accounted for based on a breakdown of checks and balances”

Being societal engagements, clinical trials rest on the trust of society; if the public loses confidence in the research process then the enterprise cannot survive. By developing the ‘rules-of-engagement’ Crawley believes GCP ensures that society can tolerate the continuation of successful clinical trials.

“All we do with regard to the ethics and regulation of clinical trials, all of GCP, is involved in building and cultivating public trust in this enterprise,” says Crawley.

Patel, drawing on his experiences as a pharmacist in the US, argues that the real issue is the public’s mistrust of the industry itself.

“I don’t see much in the public sphere about clinical trials and non ethical situations … people just don’t trust the industry and they don’t trust the drugs that they are taking or what the doctor is telling them,” he says.

The challenge, as Crawley sees it, is to build positive relationships across the industry. “What is needed is trust. We need to be able to trust each other. And the only way we can do that is first we have to know each other, and then we have to put in place systems that allow us to go back and forth in trustworthy patterns of engagement.”