Clinical Trials

Yesterday, the NIH announced that a clinical trial was opened for healthy adults between the ages of 18-55 in the Seattle area.

Here is the NIH announcement: NIH clinical trial of investigational vaccine for COVID-19 begins

And here is more information on the clinical trial for any folks that are healthy, Seattle based, and between the ages of 18-55 and interested in learning more information to participate in the trial:

mRNA Coronavirus Vaccine Study

A clinical trial is usually detailed in a document called a protocol. That protocol typically includes inclusion and exclusion criteria or the eligibility criteria for the trial that help define who participates in a study. The link below is the Clinicaltrials.gov listing of the vaccine study, which lists inclusion/exclusion criteria for the COVID-19 vaccine trial. In this particular case, inclusion/exclusion criteria help define and narrow down the definition of “healthy” in the context of this trial. Ultimately, the principal investigator, typically a physician (and other study staff) whom leads the trial at a particular institution, uses their expertise, medical knowledge, and background to determine what patients best fit the inclusion/exclusion criteria defined in the protocol.

Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) to Prevent SARS-CoV-2 Infection

A lot of active on-going clinical trials are listed on Clinicaltrials.gov

So, why is the study looking for healthy adults? Today, I’ll be sharing a bit about the clinical trial process. Prior to a medical device or treatment entering the marketplace in the United States, the FDA needs supporting evidence to show that the device/treatment does more good than harm and that it if it does more good than harm, it’s good beyond that of a “placebo effect”. Below is an image of the “clinical trial process”.

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{Source}

The clinical trial that’s currently being conducted for a COVID-19 vaccine here in the USA it’s what’s known as a Phase 1 trial. Phase 1 trials typically occur in a small group of healthy subjects so that researchers can determine human tolerable doses and how safe the investigational product or device (in this case a potential vaccine) is for humans. This is why the clinical trial process takes time. This Phase 1 trial will take 14 months.

Here is another great illustration of the process:

 

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The pre-clinical phase is data that is typically collected from insect/animal trials. If there’s sufficient data from pre-clinical trials to show promise for a particular product,  a regulatory body (such as the FDA) will review the data and possibly grant permission to move the product into the clinical trial phases (human trials). Please note that the number of participants per phase here is not necessarily set in stone (this photo is specific to a particular disease) , but the infographic provides a good overview of the phases/process. {Source}

While this clinical trial process has been successful in bringing forth a lot of life-changing devices and treatments to the market (ie. many vaccines, insulin, etc.), there are arguments that the process is too cumbersome, too costly, slow-moving, and not progressive/practical enough to meet certain demands. For example, take the case of Dr. Helen Chu, an infectious disease expert in Seattle. Per the New York Times, “In late January, the first confirmed American case of the coronavirus had landed in her area. Critical questions needed answers: Had the man infected anyone else? Was the deadly virus already lurking in other communities and spreading?

{Source: ‘It’s Just Everywhere Already’: How Delays in Testing Set Back the U.S. Coronavirus Response

So here’s what happened:

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“Federal and state officials said the flu study could not be repurposed because it did not have explicit permission from research subjects;”

What does this mean? Prior to any research study starting at any institution it has to be reviewed by an Institutional Review Board / Independent Ethic Committees (IRB/IEC). This board determines how ethical and beneficial it is to conduct a particular study. The people that compose these boards must not have conflicts of interest with the study they are reviewing. One of the documents that IRB/IEC boards assess as part of the ethical review process is called an Informed Consent. An informed consent is a document that will ultimately be presented to the potential research participant, so that the individual can understand the implications, risks, and benefits of participating in a particular research study. It’s also used so that potential participants understand that clinical research is not to be confused with clinical care.   Per clinical trial guidelines, informed consent does not end with a participant simply signing the document – it’s an ongoing discussion that must occur between the participant and study team throughout the subject’s participation in the study. Therefore, the signing of this document is just the beginning of what we call the “informed consent process”. Per FDA guidelines {Source}:

“Informed consent involves providing a potential participant with: 

  • adequate information to allow for an informed decision about participation in the clinical investigation.
  • facilitating the potential participant’s understanding of the information.
  • an appropriate amount of time to ask questions and to discuss with family and friends the research protocol and whether you should participate.
  • obtaining the potential participant’s voluntary agreement to participate.
  • continuing to provide information as the clinical investigation progresses or as the subject or situation requires.”

It’s especially important that the potential subject understands that participation in clinical research is voluntary and they may withdraw their consent at any time. Clinical trials are conducted per ICH (The International Council for Harmonisation of Technical Requirements for Pharmaceutical for Human Use) guidelines as well as the regulations as defined by a particular country’s regulatory body – in the USA it’s the FDA (Food and Drug Administration).

Based on the statement – “the flu study could not be repurposed because it did not have explicit permission from research subjects” – it seems like the informed consent for the flu study Dr. Chu was part of (“As luck would have it, Dr. Chu had a way to monitor the region. For months, as part of a research project into the flu, she and a team of researchers had been collecting nasal swabs from residents experiencing symptoms throughout the Puget Sound region.”), did not mention the use of stored samples in other studies, for other “indications”, or for future research (taking a guess here because while I have read many consents, I haven’t read this particular consent). Why does this matter? The protection of patient rights. In the early years of research there were a lot of studies that were conducted in an unethical manner (Think: Nazi Medical Experiments and the Tuskegee Study of Untreated Syphilis). In order to attempt to instill trust in the scientific and medical community, as well as to protect patient rights in clinical research came two important documents that outline the ethical principles that are to be observed for each patient/potential research participant: (1) The Declaration of Helsinki – Ethical Principles of Medical Research Involving Human Subjects (1964) and (2) The Belmont Report (1978).

As a result most country-specific clinical research regulatory bodies, such as the FDA in the USA, take participant informed consent very seriously. Now, given that we’re in a state of emergency, that brings up many questions in my industry about the clinical trial process: (1) We have known about the possibility of a pandemic in our lifetime for quite some time. Is there a way to honor patient rights & safety and expedite the clinical trial process in moments of an emergency? (2) Can the regulations be changed and amended to provide direct guidance in the context of a pandemic?  (3) How can the clinical trial process (as defined & guided in the regulations) be expedited in an ethical manner? (4) What is actually necessary to conduct a clinical trial?

I don’t have answers for any of these questions – they’re just mental musings and wanderings. Here’s a paper that provides some food for thought:

Conducting Clinical Research During an Epidemic

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Do I think what Dr. Chu and her colleagues did was unethical? I don’t know. I’ll leave that in the hands of medical ethicists and lawyers. In the meantime, I’ll leave you with the words of the modern Hippocratic Oath:

Hippocratic Oath: Modern Version

I swear to fulfill, to the best of my ability and judgment, this covenant:

I will respect the hard-won scientific gains of those physicians in whose steps I walk, and gladly share such knowledge as is mine with those who are to follow.

I will apply, for the benefit of the sick, all measures [that] are required, avoiding those twin traps of overtreatment and therapeutic nihilism.

I will remember that there is art to medicine as well as science, and that warmth, sympathy, and understanding may outweigh the surgeon’s knife or the chemist’s drug.

I will not be ashamed to say “I know not,” nor will I fail to call in my colleagues when the skills of another are needed for a patient’s recovery.

I will respect the privacy of my patients, for their problems are not disclosed to me that the world may know. Most especially must I tread with care in matters of life and death. If it is given me to save a life, all thanks. But it may also be within my power to take a life; this awesome responsibility must be faced with great humbleness and awareness of my own frailty. Above all, I must not play at God.

I will remember that I do not treat a fever chart, a cancerous growth, but a sick human being, whose illness may affect the person’s family and economic stability. My responsibility includes these related problems, if I am to care adequately for the sick.

I will prevent disease whenever I can, for prevention is preferable to cure.

I will remember that I remain a member of society, with special obligations to all my fellow human beings, those sound of mind and body as well as the infirm.

If I do not violate this oath, may I enjoy life and art, respected while I live and remembered with affection thereafter. May I always act so as to preserve the finest traditions of my calling and may I long experience the joy of healing those who seek my help.

—Written in 1964 by Louis Lasagna, Academic Dean of the School of Medicine at Tufts University, and used in many medical schools today. {Source}


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