The past has taught us many lessons, and one of them is the importance of rules, regulations, and standards. The goal of Good Clinical Practice (GCP) is to apply these collective standards to protect patients.
Let’s take a closer look at how history has shaped Good Clinical Practice, what guidelines it includes, and how GCP has changed in recent years.
The History Of Good Clinical Practice
The history of clinical research is full of methods we would not consider ethical today. For example, when testing whether catching cowpox protected someone from contracting smallpox, Edward Jenner (known as the father of vaccination) deliberately exposed an 8-year-old to smallpox to test whether inoculation with cowpox worked. An eight-year-old. While the child was fine and Jenner's work has saved thousands of lives since, this would be an absolute violation of modern ethics.
In another example, the U.S. Public Health Service took a sample of 600 Black men, 399 of whom had syphilis, and denied them access to proven treatment to study the long-term effects of the disease. The Tuskegee Study contributed to widespread distrust of the medical community that still exists among many African Americans today. This isn't the only time when researchers failed to seek proper informed consent. In 1951, a physician removed cancerous cells from a Black woman named Henrietta Lacks without her consent and grew them into an immortal cell line, which has since been used to create the Polio vaccine and many other advancements. Neither she nor her family received any compensation for her contribution to clinical research.
Thankfully, times have changed. One of the first real attempts to create guidelines for Good Clinical Practice was the Nuremberg Code, created in 1947 in response to the horrific Nazi experiments on concentration camp prisoners. The Nuremberg Code, along with the Declaration of Helsinki and the Belmont Report, still form the foundation of today's GCP guidelines.
What Are The Guidelines For Good Clinical Practice?
While Good Clinical Practice emanates from the entire body of regulations, guidelines and standards that exist globally to govern clinical research, it has long been summarized using the thirteen principles which come from the International Conference on Harmonization (ICH). ICH was intended to unify standards for conducting studies across the EU, Japan, and the US, although other countries also participated. These thirteen principles can be grouped into five concepts.
- Conduct clinical trials with an ethical eye.
- Protect human subjects.
- Design a good plan and stick to it.
- Select qualified study staff.
- Use good documentation.
Central to much of Good Clinical Practice is the principle of informed consent. Trial subjects (or their guardians for trials being conducted on children or people unable to consent) must give informed consent. This means all patients must be given the information about the study, along with the benefits and risks associated with their participation. Consent must then be properly documented.
For some research, risks may be minimal. However, it is not good practice to say there are no risks; instead informed consents should indicate "no known risks." In addition, in some research, there may be no benefit to the human subjects. That must be clearly stated in an informed consent.
In addition, proper clinical monitoring is vital. Researchers should take special care with clinical trials that present a risk to otherwise healthy participants. Vaccine trials are a key example of this. There is always a risk associated with being vaccinated against a disease, so it's vital to get detailed consent from the volunteers.
At the same time, it’s important not to take advantage of vulnerable patients and/or their parents when conducting drug or medical device trials to treat serious illnesses. In these situations, a family might agree to risks they otherwise would not take.
There is one notable exception to the informed consent rule, and that refers to emergency research. For research to count as emergency, it must involve human subjects who both:
- Have a life-threatening condition that requires urgent intervention, and for which available treatments are unproven or unsatisfactory
- Are unable to give consent because of the nature of their condition
For example, research into treating traumatic brain injuries may require doing research on patients who are unconscious or incapacitated after a head injury.
Investigators also need to be particularly careful conducting clinical trials involving children. Clinical trials in children are essential, but children are legally unable to give informed consent. Instead, their parent or guardian must give consent. Clinical providers also have an ethical obligation to do their best to ensure that the child understands, so they need to explain the trial in an age-appropriate manner. Children also ask a lot of questions, and their questions should be answered. The FDA considers children a vulnerable population and applies extra safeguards to these trials.
Other Issues In Good Clinical Practice
Informed consent is one of the most significant ethical considerations in modern clinical trials. However, investigators also have an obligation to ensure that the benefits of any given trial outweigh the risks. This may mean conducting animal trials before starting on human trials and stopping the trial if serious adverse events become prevalent.
The use of blinding in clinical trials is another important concept. The COVID-19 pandemic highlighted this issue. Because the vaccines intended to treat a major public health crisis, the FDA granted emergency authorization to several of them. The ethical dilemma was whether the trial should be unblinded once emergency use authorization was granted. The ultimate answer to this question was yes. But trial investigators often face the question of when to unblind a trial and when to end the trial and give the new treatment to the participants who were receiving a placebo.
This is particularly the case with trials that require an extended follow-up period, where the temptation not to unblind the trial may be high, but there is a point when if a trial is successful, it is unethical to continue to deny treatment to the placebo arm. Additionally, if a treatment proves dangerous, it is unethical not to unblind the study so the trial participants know what course of action to take.
What Are Recent Updates To Good Clinical Practice Guidelines?
The guidelines for Good Clinical Practice should evolve along with research methods and technology. In the past few years, there have been several updates, including:
1. The ICH E6 Guideline for GCP (R2) Integrated Addendum
This update, one of the first major changes to Good Clinical Practice since 1996, reflects changes in technology like electronic data capture, (EDC), electronic medical records, clinical trial management systems, and mobile technologies. This addition addresses gaps identified in 398 GCP inspections by the European Medicines Agency.
Key changes focus on better defining the responsibilities of sponsors and investigators, using a risk management approach to study design and monitoring, and improving data integrity, especially when using electronic systems.
2. Revisions To The Common Rule (45 CFR Part 46)
This revision, which became effective in 2018, was intended to better protect human subjects while reducing burdens for investigators. It eliminates the need for continuing review of minimal-risk research and allows researchers to receive broad consent for data or biospecimens to be used in future research. Investigators should update informed consent documents to state whether the patient’s specimens will be used for commercial profit and if the patient will receive royalties. It should also state whether clinically relevant research activities will be disclosed to patients and if the research might include whole genome sequence.
3. The 21st Century Cures Act
This act, which became law in 2016, includes new Health and Human Services guidelines for remotely accessing personal health information to comply with the HIPAA Privacy Rule. It also requires NIH-funded clinical trials to share scientific data from their research.
4. 21 CFR Part 11
This update further elaborates on guidelines for using electronic signatures, including what methods researchers may use, how the FDA will inspect electronic systems, and what access controls sponsors should use for mobile technology used by study participants.
Sponsors should validate electronic systems, ensure they have processes in place to control changes, and maintain an audit trail of any changes made during the trial.
5. Final Rule Updates To 21 CFR 812
This rule, issued in 2018, updates the FDA’s standards for accessing clinical data from investigations inside and outside the US to ensure the protection of human subjects and ensure data integrity.
It requires medical device sponsors to include statements and information about how their studies conform to GCP. This must be included if they are requesting an investigational device exemption, premarket approval, or humanitarian device exemption, and also with requests for de novo classification, premarket notifications, and product development protocols.
In the EU, recent changes have also focused on medical devices and in vitro diagnostic devices. This adds a new pre-market scrutiny mechanism for high-risk devices, improves transparency through a comprehensive EU database, and introduces an implant card for patients containing information about implanted devices, among others.
How To Apply Good Clinical Practice
Good Clinical Practice ensures medical science moves forward while protecting human subjects. It's vital for investigators to ensure that they prepare for the trial properly, obtain informed consent, clinically monitor their research subjects, handle blinding and unblinding of trial data ethically, and keep abreast of evolving standards, regulations, and guidances. Good training, solid third-party oversight, and thorough documentation also make a huge difference.
As a full-service medical device CRO, IMARC can help both sponsors and sites follow Good Clinical Practice guidelines. That includes helping sponsors develop a risk-based monitoring plan, enforcing quality standards, training your team in the FDA regulations and how to apply them, and auditing your sites to ensure they pass inspections.
We offer GCP training in person and online, including a GCP course that is a great introduction for new research associates or good review for veteran professionals.
For more information about recent changes to GCP guidelines in the U.S. and the EU, download our white paper.