Monday, June 29, 2015

Q & A - Clinical Research - Food Allergy Treatment Talk

This past week, I led a question and answer session with the private Facebook group, Food Allergy Treatment Talk. The following Q&A is published with kind permission by the administrators of the group. Much more discussion followed that is not published on this blog to keep responses anonymous. I highly encourage anyone thinking of participating in clinical research to take a look. We only advance our understanding, treatments, and potential cures through those choosing to participate in clinical research - altruism at its best!

This discussion couldn't have come at a better time as FARE announces the beginning of a clinical network that will help organize and speed discovery toward treatments and cures. I'm sure more will follow on how this network will achieve these goals!

Questions and Answers

1)   Clinical studies vs. clinical trials: is there a difference?

Yes! While these terms tend to be used interchangeably for those outside of the medical/research community, they do in fact have different meanings. Clinical studies – Any research that uses human volunteers. There are different types of “clinical studies.” One very specific type of clinical study is the clinical trial. In other words, if clinical studies are like cars, then the clinical trial may be considered a Cadillac. Clinical trials assign people (i.e. participants or test subjects) into particular groups at the beginning of a study according to a defined research plan and follow them through time. Another type of clinical study, an observational study, does not assign patients into treatment groups at the beginning of the study. Participants are often patients who are receiving routine medical care and the researchers look at outcomes after the fact. Sticking with our car analogy, observational studies might be a Chevrolet.

Clinical trials (a “Cadillac” study!) may get at cause and effect relationships and whether a treatment may be safe and effective. Observational studies (a “Chevrolet” study) provide associations (correlations) and may hint at cause and effect relationships, but don’t by themselves test the safety and efficacy of a treatment. Both types of studies are important: one of them is more expensive than the other and both may be considered a “good, well-designed study.” Getting a “lemon” is possible for each type.  

Food allergy studies may be a clinical trial or an observational study.

Example clinical trial for food allergies: Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial.

Example observational studies for food allergies: The ever-so-maddening association between dishwasher use and allergic disorders.

A good resource describing difference in clinical study types:

2)   What are the safety protocols for a new drug prior to getting to human trials?

Before a drug is tested in people (pre-clinical studies), it is first isolated and purified. It is explored using a minimum of two different animal models - one rodent and one non-rodent model. It is also tested on human cells in vitro, which means that scientists grow cells in a dish and look for any effects – good or bad – that the drug may have on human cells. Scientists then use the data on how the drug effects the animals and is processed/broken down in animal models to make an estimate of dosages and timing of dosages to use in human trials.

Before a drug trial begins, the research sponsors must file something called an Investigational New Drug (IND) application with the U.S. FDA that must be approved (many other countries have a similar process). This will include data from the pre-clinical studies.

On top of this, all aspects of the study parameters and its management are thoroughly documented and submitted to an Institutional Review Board (IRB), which is overseen by the U.S. Dept of Health and Human Services’ Office for Human Research Protections. An IRB consists of multiple individuals not involved with the study – both experts and non-experts from the community - and who should not have conflicts of interest. They review and must approve all research studies involving humans before any study begins. Their primary objective is to protect people’s health and well-being. Risks and potential benefits are weighed in this decision and the IRB ensures that participants are fully informed and that participation is voluntary. The IRB continues to monitor the study throughout its duration. If a study is approved, the IRB will determine how frequently they will monitor the study, but the minimum is once per year for low risk studies, more frequently if there are more potential risks.

3)   How long or what are the safety protocols for the drugs from the human trials to FDA approval?

Part 1: How long for FDA approval.
This is a great question and certainly varies quite a bit from study to study. Getting a new drug to market can take upwards of ten to twenty years (more when all of the preclinical/basic scientific findings are considered!).

A tangible example for asthma and allergy is Xolair (omalizumab), which is an anti-IgE antibody therapy. IgE was first discovered in the 1960s with the following decades spent understanding how it worked. Anti-IgE therapy was first proposed in the late 1980s/early 1990s as a treatment for asthma/allergy. It was approved by the U.S. FDA to treat moderate to severe allergic asthma in 2003 and chronic idiopathic urticaria in 2014. It is currently in various phases of clinical trials to treat food allergy in combination with oral immunotherapy (OIT). I’m guessing some in this group may be involved in those trials?

Part 2: Safety protocols for the drugs from human trials to FDA approval.

For a new drug, there are four phases of clinical trials. Each phase has a slightly different objective, but safety is first with continual oversight of patient health and well-being by the study administrators, the IRB, and annual reports to the FDA. A study may be stopped during any phase if there are significant adverse events. On the flip side, a treatment could be so effective that it would be considered unethical to withhold the new treatment from people in a control group. Even after a drug is approved and on the market, the safety and efficacy is still monitored (Phase IV). Vioxx is an example that comes to mind for a drug pulled from the market over safety concerns. There is a fabulous infographic from the FDA describing the various stages of drug development.

Additional info if there is time or further questions:
Phase I: often called “first in man studies.” These are small and aimed at determining drug safety and side-effects. They are NOT intended to assess whether the drug is an effective treatment. Typically healthy, unaffected volunteers participate (i.e., non-allergic individuals if we’re talking allergy treatments) and receive increasing doses of the drug while assessing many quantitative measures along the way, while noting any adverse effects. These studies help establish how the human body is affected by and processes the drug. If there are major safety concerns, the drug will not move on to Phase II.

Phase II: Again, these are small studies, but their primary objective is preliminary evidence that a drug is actually effective. They also monitor for any adverse effects just as Phase I studies do. If there is no evidence that the drug is effective, then it will not move on to Phase III.

Phase III: Large studies (typically several hundred to thousands of people) that aims to determine if the drug is an effective treatment! Of course safety is still monitored along the way. These are also known as the randomized controlled clinical trial, the gold-standard for scientific evidence. If evidence shows the treatment is effective and safe, a drug will eventually gain FDA approval for widespread clinical use.

Phase IV: This is after FDA approval and the drug is available to the masses. Effects of the drug and any adverse events are reported and may warrant follow-up. Even large Phase III trials may not be enough to catch rare side effects in multiple populations of people.

4)   How does a trial determine how many people are needed for the results to be statistically relevant?

Fabulous question for all of the math/statistics lovers out there! Researchers/statisticians will use a statistical computer program to help them assess an appropriate number they need to recruit.

Main factors that go into this estimate:
1.    Effect size estimate between the new treatment and the control. For example, an OIT study may predict an 80% difference in the number of patients who develop sustained unresponsiveness to eating peanuts in the OIT group compared to those receiving a placebo. Large effect sizes mean fewer patients needed, while a smaller effect size means more patients.
2.    Desired level of statistical significance (standard is 5%). This means there is a 5% chance of getting a statistically significant result when there is in fact no true difference (i.e., false positive). While 5% is standard, sometimes studies while go more stringent to 1%. If a smaller percent chance of having a false positive is desired, then more subjects are needed.
3.    Desired power of the study (typically set at 80-90%). This means there is an 80% (or 90%) chance of finding a significant difference if it is truly there [i.e., 20% (or 10%) chance of a false negative]. Achieving a desired power of 90% would require enrolling more subjects than 80%.
4.    Estimate of people that will drop out or not comply with the study. More people must be enrolled in a study than are ultimately needed in order to account for attrition.

Of course these are estimates that make certain assumptions (which may be right or wrong), so the number of participants is something evaluated as the study is ongoing.

5)   If participating in a clinical trial, is the cost covered, including travel expenses?

Many studies will have some form of compensation for participating (possibly travel expenses), but not all. How and if participants are compensated is all laid out in the consent forms the participant or legal guardian must sign before participating.

If anyone who has done a clinical study is willing to share, feel free to share your experience with study compensation. I honestly don’t know the answer for typical food allergy studies.

6)   During trial or studies, do the docs mention the consequences of the study? Like for OIT, do we know what potential side effects are mentioned?

All known or suspected side effects must be disclosed. They typically discuss what the possible benefits are as well as the risks. This information will be provided in the consent forms signed before participation. In the case of OIT, they will definitely lay out what the risks are and also give some kind of indication how frequent particular adverse events may be (e.g. anaphylaxis, hives, etc). In general, the earlier the study is in clinical trials, the greater the uncertainty and potential for unforeseen risks. If you are considering a Phase III trial, definitely try to find the published primary scientific findings from earlier phases where all adverse events will be reported. Again, because these are investigational treatments, it is challenging to predict.

By the way, you can look up clinical trial in the U.S. at

7)   If you are unable to complete the trial, do you continue the dose you left at, or are you just done? Is it costly to continue when a trial is complete?

This is hard question to answer because it highly depends on what the reason for withdrawing is (or being terminated) and what is being tested in the study.  If the reason for withdrawing is a serious adverse response, I would guess most aren’t too keen to continue with the treatment! I’m reading between the lines a bit here, but I think your question may be getting at OIT “doses?” If this is the case, there may certainly be a reason to continue in spite of adverse reactions at a higher dose. I highly recommend Caryn Tatelli’s blog, Eating Peanut, of her daughter’s experience in an OIT + Xolair trial giving a really honest and informative account. I don’t have direct experience with food allergy clinical trials, so getting information from those who have been part of studies is incredibly helpful! Again, not all studies will handle things the same way, so it is important to understand the consent form and ask lots of questions.

As far as cost after a trial ends, it all depends on the study and treatment. The cost of all study related treatments are generally covered, but there are certainly situations where there are shades of gray. In those cases, it is helpful to discuss potential follow-up with those who are in charge of the study, your regular health care providers, as well as your insurance company.

8)   What typically happens to a patient after a clinical trial ends? Does treatment end?

If there is evidence that a treatment is effective, then it is typically continued. Studies will generally have some kind of follow-up, which should be laid out in the consent form before the study begins.

9)   Where does funding come from clinicals? Many seeking FDA approvals are funded by companies seeking to make $--an investment. How does it work with universities and government funding? They can’t keep researching the same thing, so they have to look for angles and write grant requests?

Funding for clinical trials comes from multiple sources: private industry (e.g., pharmaceutical companies), government funding (e.g., NIH, Department of Defense, the National Science Foundation), private investors or foundations (think, Sean Parker!), non-profit organizations (e.g., FARE, AAFA) or trade groups (e.g., the National Peanut Board). 

The following paper shows the estimated contribution to “biomedical research,” which is a broader category than “clinical trial.” If you scroll down the paper in this link, there is a really nice graphic breaking down the contribution by each major funding source. That being said, as research moves closer to the clinic in trials, private industry foots more of the cost. Phase III studies are large and expensive!

You are correct in that research moves in increments, so researchers look to extend findings or ask further questions based on previous results in grant proposals. While discovering something new is what everyone wants, it is also crucial that different research groups look to replicate previous findings. Reproducibility is a crucial part of science. How many times have we seen reports about coffee being “good or bad” for you? Kind of hard to trust results when this happens. It’s the nature of the beast unfortunately.

10)How much does it take to get FDA approval? What size do the studies need to be? I have read hundreds of millions of dollars to get through all the committees, reviews and big studies.

It depends on the drug, but you are absolutely in the ballpark for costs to get drugs into the marketplace. Some are pushing into the billions of dollars!

11)What criteria do organizations like FARE consider when determining research studies to help fund?

They are certainly looking for scientifically sound proposals first and foremost, but on top of this, they are funding studies that fit with their 2013 strategic plan. I would encourage everyone to spend some time reading this document!

If you look at the list currently being funded, the bulk of their research budget appears to be aimed at short-term treatment solutions with uncertain long-term outcomes (e.g., various flavors of immunotherapy). That being said, prevention and a cure is certainly on the radar. I will also mention that there are still many discoveries yet to be made into how the immune system works (i.e., basic science or pre-clinical research studies). There is still so much we do not understand! The jury is still very much out on whether immunotherapy will ultimately produce long-term tolerance (maintenance doses no longer needed). As all news articles like to end, “But more studies are needed.”

12)On average, what are the start-up costs for a clinical trial? Research study? What happens if a study runs out of funding before completion?

It depends on the study. Earlier studies in the research pipeline are not as costly as later studies. Earlier studies typically run several hundred thousand dollars at the low end to several million. I can tell you that I had confirmation from the NIH that they contributed about $15.5 million to the recent LEAP study, and they weren’t the only funding source!

As to what happens if funding runs out before completion: I do not fully know the answer. I can tell you that federally funded research grants have a way to request an extension to complete the trial under certain circumstances. I do not know what the situation is for private funding sources.

Some additional sources:  Searchable database of U.S. clinical trials.

Protecting America's Health Through Human Drugs. Published 2006 by the U.S. FDA (publication previously known as From Test Tube to Patient.). Describes the process of getting drugs to market.

Concise Guide to Clinical Trials  by Allen Hackshaw. A nice book for those who want to dive a little deeper into understanding the inner workings of how clinical trials are conducted.

Chasing Medical Miracles: The Promise and Perils of Clinical Trials by Alex O’Meara. This book gives a first-hand account of a journalist participating in a clinical trial to transplant pancreas cells in hopes of curing his type I diabetes. He tells his personal experience while providing history and facts about clinical trials. An approachable, interesting way to learn more about clinical trials.


  1. These are good information. I am so outdated with what's happening in the medical world nowadays.

    But trial with humans, is that still an ongoing argument? Really risky, right?

    Well, thanks for this.

    1. Thanks, Lux. Clinical trials certainly carry greater risk than standard of care, but foreseen risks/benefits will be laid out before agreeing to be part of trial. I would say some studies carry greater risk than others and it's not a decision to take lightly. Then again, regulation/oversight of trials, while not perfect, is safer than in the past!

  2. Jessica,

    You knocked it out of the park with this one! This should be made into an email or part of a FARE conference lecture. You brought it down to such understandable levels and I appreciate that to no end.

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