[12 MIN READ]

While the mission of clinical research is to advance the practice of medicine, it is an extremely daunting task to not only manage clinical trials, but to also oversee them to keep patients safe and reduce risk. In a review of numerous malpractice cases related to clinical research, I have found several common denominators and opportunities to improve patient safety.

The issues that arise from clinical trials are not typically intentional; they are simply intrinsic to the complexities of the system. Under the best of circumstances and in many cases by design, patients have significant problems and are randomized to receive a trial drug. This population is inherently at risk. Additionally, many medical professionals are not trained to conduct appropriate, safe, well-organized clinical trials. These factors along with others I will outline have led to an increase in patient injury, federal and legal scrutiny, and obviously, litigation.

The Gelsinger Case

Jesse Gelsinger was an 18-year-old male who suffered from a metabolic disorder called ornithine transcarbamylase deficiency (OTC), an enzyme deficiency. His case was not severe; he controlled it with a low-protein diet and drugs and was doing okay. OTC is genetic and results in a failure to break down ammonia. Ammonia needs to be broken down in the body and eliminated; otherwise, it leads to neurologic problems, including coma and death in serious cases. This case was settled, so the depositions or litigation transcripts are not all available to review. From my own knowledge of the case, Jesse volunteered to participate in the clinical trial, although he knew the study drug would not benefit him. He thought there was little risk and that his participation might benefit those yet to be born with OTC.

Researchers take the virus and inject in each of the strands of DNA that produce this enzyme; they fill the virus full of it, and then they inject the virus into the body. Jesse was infused with trillions of particles of an adenovirus vector, each carrying DNA that would produce the OTC protein.

Now, imagine you are a principal investigator. You have delegated your responsibility for informed consent to a tech or a nurse outside the clinical team. Imagine explaining the adenovirus vector to a patient. It might go something like this: The virus is going to infect all the cells of your body, after which the cells will attack it and kill the virus; they will open up, and the DNA will spread all over; and hopefully it will merge with your genome. That will then start creating the enzyme, and that will help your clinical condition.

This is a complex and difficult explanation. The adenovirus vector was a new gene delivery mechanism, and it turned out to be more toxic than other vectors used in gene transfer. Within days of the injection, Jesse suffered from liver toxicity, a blood clotting disorder, kidney failure, lung failure, and finally brain death.

Common Allegations Related to Clinical Trials

Conflict of Interest

It is important to note who is originating, conducting and delivering clinical trial research. There was a massive and dramatic web of conflict of interest in this case, which makes it a good example.

This trial was conducted at the Institute for Human Gene Therapy (IHGT) at the University of Pennsylvania (Penn). Dr. Wilson was the principal investigator. Dr. Wilson was the founder and 30% owner of Genovo, the company that developed the trial medication. As Genovo succeeded, Dr. Wilson succeeded financially or in other ways – an obvious conflict of interest. He was an employee of both Penn and Genovo, and he ran the IHGT – certainly the appearance of a conflict. Also, Genovo gave millions of dollars to the institute. Another conflict here was that Penn, Dr. Wilson and Genovo would all benefit financially from the success of the new viral vector. This adenovirus vector was a new delivery mechanism; they would have been able to patent it, and all would have benefited from that.

There are many instances, of course, when the conflict isn’t so obvious. Each of those needs to be investigated and evaluated by the Institutional Review Board (IRB). However, it can be difficult to not have a conflict. For example, if you’re a researcher who discovers something interesting and new such as an adenovirus vector, you probably have something to do with the company who’s creating it for you; and it’s difficult to be completely removed from the subject of the research. Your discovery could be huge if it works and everything is done correctly, but it’s tough to do everything right in this area.

Generally, there has been a significant increase in the number of trials funded by for-profit organizations. As a result, JAMA and others have investigated whether this is impacting research. For-profit company research is 5.3 times more likely to show favorable benefit for their product compared with non-profit. A study in The American Journal of Psychiatry found conflict of interest to be prevalent among psychiatric clinical trials and to be associated with a greater likelihood of reporting that a drug is superior to a placebo. Readers need to evaluate the statistics and results in clinical research reports closely to ensure they truly understand the validity of the conclusion.

While most cases of conflict are subtle, bias and conflict are still found in the research community. The federal regulations and academic institutions have become much more educated and vigilant in identifying them.

The IRB Process

This case serves as a marker for where we find the major problems and reasons for patient injuries – the IRB process itself. The Penn Institutional Review Board (IRB) approved the study. Penn has a Conflict of Interest Committee; it asserted that a conflict may exist, but the university allowed the trial to proceed.

Given that conflict of interest, how did the committee allow this trial to proceed? Maybe they didn’t have all the facts or they were under significant political and/or financial pressure to let this trial move forward. These trials involve millions of dollars; there was a significant financial relationship between Genovo and the IHGT, if not Penn. This is common and exists in many academic facilities. The IRB process is one of these key issues in analysis of all these cases. In this case, either the IRB approved an inadequate informed consent process initially, or there was not ongoing monitoring of the trial to continuously evaluate risk/benefit and modify the informed consent.

Inadequate Informed Consent

Inadequate informed consent is the next major issue and another common denominator in many of the cases I’ve looked at. Patients were shown an informed consent document that did not adequately inform regarding the process and risks of the adenovirus injection: 1) Dr. Wilson’s conflict was not adequately explained; the study subjects should have known there was a conflict of interest. 2) The informed consent form was modified to remove the death of animals (monkeys) that were injected with the virus. 3) No mention was made of prior patients who had serious adverse effects; this should have been part of a least a modified informed consent process.

Violations of FDA Guidelines

Violation of federal guidelines is another part of many cases, including this one, especially in this highly regulated genetic research area. The FDA/Recombination DNA Advisory Committee (RAC) was not informed of a change in the method of viral administration. Investigators did not report that prior patients suffered from liver toxicity and that the study should have been put on hold. And they failed to follow the study protocol. Researchers, IRBs and academic facilities need to be familiar with and adhere to those federal guidelines.

Violations of the Study Protocol

Failure to follow the study protocol is another critically important issue; per the protocol, they were to treat two women before treating a male (Jesse). There was also a study violation; this had been demonstrated to be liver toxic, and Jesse had elevated liver enzymes, which meant that he already had a problem with his liver and should not have been injected. Incredible!

The conflict of interest with Dr. Wilson was apparent, and I think the reasonable person would have recognized it and done something about it. Informed consent wasn’t good enough, but problems in the provision of informed consent can be subtle. For the most part, no one is intentionally withholding information from patients, but there are opportunities for improvement here; it speaks to education and coordination of the team. If you have a study protocol, just follow that study protocol; deviations are inexcusable. Bottom line: you have to stick with the study protocol.

The Aftermath

Following Jesse’s death, an independent panel of experts concluded that the IHGT was not capable of complying with federal regulations governing clinical trials. The FDA stopped all human clinical trials at the institute. This is huge; it’s a major financial blow to an institution that depends upon funding research.

As a result of this case, the American Society of Gene Therapy said: “All investigators and team members directly responsible for patient selection, the informed consent process and/or clinical management in a trial must not have equity, stock options or comparable arrangements … in companies sponsoring the trial.” This was an important case, and folks responded to what happened.

Lack of Training

There is a fundamental flaw in clinical research. The clinical team receives no medical school training in the broad range of logistics required to run a clinical trial. This is a group that delegates responsibility for critical actions, at times to people who don’t understand key issues. In this case, if it went from Dr. Wilson to an advanced practitioner working with techs, they may not have adequately conveyed what an adenovirus vector is.

Additionally, clinicians as a population are not known for communication skills. However, communication skills are critical if we are going to properly run a clinical trial.

Magnitude of the Research Challenge

The research community is enormous. There has been a dramatic growth in the number of clinical trials, many of which are now sponsored by for-profit organizations. Conflict is often built in, sometimes without an actual awareness that it’s there. IRBs are overworked, often undereducated, and under pressure to approve from many directions.

In 2018, there were 45,000 active clinical studies in the U.S., and all needed a principal investigator. The research team for each trial varies, but let’s estimate 10 per team. This comes to approximately 450,000 researchers – including advanced practitioners, nurses and techs—and they’re working with some people who aren’t even on the research team. There are likely millions of patients enrolled.

The Outcome

Many healthcare practitioners are ill-prepared for the complexities involved in properly delivering a clinical trial protocol. There are complexities; in the best of situations, there are numerous roads to error.

It’s important to note that these issues are not intentional; they’re medical errors. These are dedicated people who want to make the world a better place with clinical trials. Education surrounding common errors can help researchers keep them front-of-mind so they can be avoided. Certain factors could be built into the electronic health record (EHR), including protocol assistance, inclusion and exclusion assistance, etc. While today’s popular EHRs don’t include these, we can keep them in mind for future enhancement.

Like medical malpractice, there are far more errors than lawsuits. Lawsuits are good markers though; they help us with certain fact situations. Most errors are hopefully not harmful, but many occur in the daily process of delivering a clinical trial.

Resulting Litigation

In general, clinical research allegations include wrongful death, negligence, informed consent, assault and battery, and infliction of emotional distress. Not respecting the dignity of the individual and ethics reports from the Belmont Report and the Nuremberg Code are often mentioned in the allegations of wrongdoing.

Making Clinical Trials Safer for Patients

To run a trial correctly, your organization, the IRB and the research team need to ensure the following:

• There is no conflict of interest.
• The risk/benefit is appropriate.
• Informed consent truly delivers the risks, benefits and alternatives.
• The protocol is followed to the letter.
• Changes are made to the protocol when something occurs in the research to change the facts. Some research has to be stopped because people are being hurt, and some trials are stopped because they’re so good it’s ridiculous to randomize people into which arm gets placebo.
• Changes are communicated back up to the principal investigator and back up to the IRB.
• Change in patient condition is monitored and responded to. There are millions of patients. Some studies aren’t going to have an impact on patient condition, but many will have a huge impact; in those studies, patient condition must be monitored and responded to.

Golden Rules of Clinical Research

There are several opportunities to keep patients safer and avoid exposure to liability in clinical trials. Consider looking at your whole clinical research process from start to finish. Ask these questions:

• Who are your principal investigators and what are their conflicts of interest? What are you doing about them?
• How are you delivering education to the research team, especially the right and wrong way to present informed consent documentation?
• Who is delivering informed consent? What steps are you taking to make sure that your next patient truly understands what the trial, their options and alternatives?
• Who is on your IRB?
• How do you confirm your IRB is educated, organized, has the time, isn’t feeling political pressure, isn’t feeling financial pressure, etc.?
• What oversight do you have? Maybe a Conflict of Interest Committee? Go to the Ethics Committee initially to keep the IRB on task?
• What happens when there is a change in patient condition? What happens when there is a necessary change in protocol? Are there changes in protocol that are happening without the IRB or are the federal agencies involved?

Additionally, IRB members must: understand roles, risks and responsibilities; avoid even the appearance of conflict; perform a careful risk/benefit analysis for each clinical trial; approve only informed consent documents that truly convey risks, benefits and alternatives; see evidence that there is a process for appropriate delivery of informed consent; and develop clear guidelines for when investigators must return to the IRB for ongoing oversight and modification.

If you’re a participant in research, you must: ensure that the study has been approved by an appropriate IRB; ensure that you’re covered for problems that may occur – consult an attorney or insurance carrier to determine whether your current insurance policy covers claims related to clinical trials; employ qualified and certified clinical trial coordinators to help administer the trials; ensure that the potential participants are fully and properly informed; and ensure that “alternative treatments” is a section of the informed consent document and that it’s clear and complete. Only participate in studies where the providers and their practices have sufficient expertise and resources to deliver the clinical trial. Refuse to accept any studies in which you believe the risk to participants outweighs the potential benefits and scientific value. You may be asked to participate because someone up the chain thought that the benefit outweighed the risk; however, you may not believe that. Ask questions about it. Go back and sit with the committee and talk about it.

Clinical research is a positive activity for the medical community. It brings in research dollars and builds reputation. It also helps patients live longer. Still, the process of clinical research is complex and needs to be executed correctly. Because of all the opportunity for injury and harm to occur, we need to work together to make the process safer for our patients.