Evolution of Research Inclusion

Podcast Transcript

Announcer:

Welcome to Cleveland Clinic Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Natalie Salvatore, MSN, MBA, RN:

Hello, my name is Natalie Salvatore. I'm a registered nurse at the Cleveland Clinic in the Heart, Vascular ND Thoracic Institute.

Eileen Hsich, MD:

And I'm Dr. Eileen Hsich and I'm the Medical Director for Heart Transplant at the Cleveland Clinic and NIH researcher.

Natalie Salvatore, MSN, MBA, RN:

Dr. Hsich, can you tell me a little bit about some of the guidelines that are in place when we're talking about clinical research and trials? What kind of structure is there to help guide clinicians when they're investigating different things?

Eileen Hsich, MD:

What an amazing question. I think it's important for people to recognize that the reason we have guidelines is to standardize care across the US as well as internationally so that we have the best outcomes for our patients. But I think it's important to remember that these experts that have created these guidelines are basing them on landmark clinical trials that include and exclude certain cohorts. And I think what people don't realize is that the patient in front of you may not represent the patients included in the clinical trials. And so that is really the most essential piece to recognize who has been included, who has been excluded, because the experts that write these guidelines have to have data-driven information to actually move our field forward and give the best advice. I think it's also important then when we think about things like heart failure, which is a disease that increases in prevalence as we get older, that people need to realize that despite the fact that this disease affects the elderly in such high percentages, that patients over the age of 75 are often not included in the clinical trials.

So, it is important to recognize that the guidelines can only reflect what data exists and it is our responsibility if we want to improve the guidelines that we need to include more patients that represent the population in clinical trials. Right? You want the disease prevalence to really reflect the prevalence of patients out there with those diseases and make sure that the treatment is specific for them. And so, we all need to start including and thinking about that and trying to reach out and educate our patients to let them know that this hasn't included you and we'd like you now to consider these trials. And I think that's really the biggest message I want people to recognize that until research had been done, people really didn't understand that there were differences between women and men with response to treatment and prognosis. And the same is true for people of different races and ethnicities and different ages.

Natalie Salvatore, MSN, MBA, RN:

I think that's a great point that you make to really look at and truly understand the differences in the patients that have been involved in past trials. And you mentioned the one piece of advice that you would offer moving forward would be to expand that inclusion criteria and really look at the patient that you have before you.

Eileen Hsich, MD:

I think that's important. I mean, I think that the inclusion has always included everyone from different race and ethnicities and has included, at least now in the current system, includes women and men. I want people to recognize that there is a history here that lets you know how long it took for us to start including women and elderly patients, so that most of the clinical trials that were done earlier did not include women and elderly patients. Early on a drug called Thalidomide actually caused birth defects and because of the birth defects, women that were childbearing ages were prohibited to participate in clinical Phase I trials, which are safety trials for new drugs. And that was a mandate by the FDA in 1977. That was meant only for new safety net clinical trials, but because of the concern, hospitals and different medical centers were afraid to take on that responsibility of including women.

And so, in the 1980s, when we think about the first landmark trial for heart failure that actually showed mortality benefit of a drug, the important thing to know is that a Veteran's Study called the VHF study, and I think it's important to recognize that women were not included in this trial because of those concerns. And from 1980 to 1990, there were very few women enrolled in clinical trials. So that in 1983, the US Public Health Service Task Force on Women's Health Issues published a report focused on health services for women and the elderly, research to better understand sex and gender differences, data collection was needed by age, sex and race across all socioeconomic backgrounds. And finally, the fourth request was that more women at all levels of healthcare were needed so that the provider should look like the patient. This report influenced the NIH that basically funds clinical research and the FDA that basically approves drugs and devices. It influenced them to review their policies.

So, it was in 1983 that the FDA surveyed their new drug applications and recognized that there was an under-representation of women and the elderly in cardiovascular studies. 1983. So, we're not talking about hundreds of years ago, we're talking about 40 years ago. And there were a lot of landmark studies prior to that. So, it's important to recognize that as they were coming through, they were under-representing women in the elderly. 1986, the NIH developed a policy to include more women in clinical trials. And in 1989, the FDA included a statement to encourage elderly patients to be included in new applications of devices and medications. And they defined the elderly as greater than 75. Just stating that we actually should do something doesn't mean it will happen. And in 1990, the US Government Accountability Office reported that the NIH was not effective in their policy to change the inclusion of women in clinical trials.

They specifically said that there wasn't an update in the grant application to reflect the new goals, there was inconsistent informing of grant reviewers, and they did not enforce the researchers to report sex specific data. So that means that there was very little sex specific data being actually published. In 1990, this did not go unnoticed. So right after the Accountability Office wrote up their report, Congress passed the Women's Health Equity Act to create an Office of Women's Health to provide health services and include females in NIH funded research to improve healthcare. And it wasn't until 1993, so really about around 30 years ago that the FDA rescinded the 1977 ban prohibiting women in Phase I clinical trials. And at that time, Congress, to ensure that all this took place, passed the NIH Revitalization Act to ensure that policies were enforced by law. In 2000, the US government did one more accountability report and recognized that the NIH had achieved their goal of including more women and the elderly.

So, we are improving, but we still need to do more. And you can imagine if it has really only been since 2000 that we've been successful in actually starting to include certain groups that these landmark trials for which our guidelines are written may not reflect our patients in front of us. We're not going to repeat studies that were for medications or devices in subgroups. We're not going to randomize them anymore. And so, it's important to recognize that we have a responsibility as care providers to encourage our patients that are people of different backgrounds and ages, and also women to participate in future studies so that they can be represented, and we can ensure that the outcomes and the treatments actually improve their care.

Natalie Salvatore, MSN, MBA, RN:

Now, what advice would you give to your provider colleagues on how to approach this topic with a patient? How would you guide your colleagues to ask the patient or explain it to the patient? Many of our patients are fearful of being involved in trials or research. What would you suggest helping ease their fears and concerns?

Eileen Hsich, MD:

Wow, that's a great question. We've done it very well when we have focused studies actually on specific groups. And I think that that is an important thing is that conversation piece and different populations really need a little different approach. But I think what I always say to patients is that we all hope somebody else is going to participate in a trial and you also hope that actually the medication or device that you're getting is going to work for you. So doing epidemiological research where you just collect the data and follow it has really started to open our eyes with regards to actually differences based on age, sex and race. I mean, I think that if I use heart failure as an example, once we started to really explore, we realized that women and men develop heart failure for different reasons, different risk factors as an example. So, women are more likely to have hypertension as the underlying cause, where men are more likely to have myocardial infarctions. Women are more likely to develop heart failure at older ages, yet men are actually more likely to develop it younger. Women are more likely to develop heart failure with higher ejection fractions, yet men are more likely to have lower ejection fractions. And even when we get to the level of just looking at an acute event, when a patient with heart failure decompensates and needs hospitalization to actually treat their fluid overload, the natriuretic peptides are higher levels in women compared to men when you stratify the data based on EF, because there are also known differences based on EF.

So, there's importance to recognize that there is value in including more patients and that the prognosis is different. The African American population has much worse prognosis with many different cardiovascular diseases and a long history in research of not being fairly treated. And so, there were concerns whether people were going to do harm rather than good. And there's a lot of regulation to prevent any of those things from ever happening again. But because they happened, we have to recognize that they're going to be fearful. And yet we want to only make sure that we can improve the outcome that currently is so different and worse for that group.

So, it is important I tell them that we need to all participate and I let them know that I've participated and some of the things that when I participated, I don't get direct benefit, it affects somebody else. And so, I'll give an example, which is a little more personal, but when I had children, because I was older, they wanted to actually know how do you find out if your fetus has Down's and can you do an ultrasound to determine this rather than an invasive test? And so, I participated in studies that I didn't get any feedback from, but yet benefited actually the second time I had a child. But it also now is included in medical practice so that we reduce the need to do invasive testing to look for any genetic problems. So, it's not that you may not benefit, you may benefit later again, but it's important that we all participate and recognize that it is a greater good that will help our children and future generations.

Natalie Salvatore, MSN, MBA, RN:

That is some great advice that our provider colleagues could use to educate and work with patients to help ease some of their concerns. And I think you mentioned one really good point about the protections in place so that when we are doing research or trials, our patients are protected.

Eileen Hsich, MD:

Natalie, I think it's also important for people to recognize that not all clinical trials are actually medications or devices. It could be diagnostic testing so that your risk is really low for many of these studies. So, it's important for people to recognize that not all trials are the same, that they carry different risks. And I bet you patients may not be aware that there are many safety guards during a clinical trial, including actually safety committees that are evaluating at very specific time points, early, mid and late to make sure that there is no poor outcomes, so that when they start to see a concern, you'll see trials end prematurely. It's not uncommon. Beta blockers are a perfect example of how they actually were so powerful for heart failure, for improving mortality and morbidity, that they stopped many of these clinical trials to make sure that all patients were getting the best therapy. Super important.

Estrogen is a perfect example. For many years, estrogen was promoted as a drug to prevent heart attacks. But until we actually included women and did a randomized, well, they are for women, but randomized trial, we didn't know that there were potential adverse events including heart attacks. So myocardial infarction. And I bring that up to my patients as well to recognize that when we do epidemiological studies, there's limitations and that we benefit from it. But not all trials are medications, there are many that actually are just to improve quality of life, to understand quality of life and to actually do better diagnostic testing so that we can actually detect a disease earlier.

Natalie Salvatore, MSN, MBA, RN:

I think you brought up a good point too, the discussion between the patient and provider, that shared decision making. I think it's so important that our patients realize they're not alone. Just because they may enroll in a study or trial, it does not mean that's the end. They are continuously working with the healthcare team, they're not on their own. So, I think also emphasizing that that support system is still there is so important.

Eileen Hsich, MD:

The other thing that is commonly stated is you get better care. So, you have more frequent visits, which may be annoying to a patient, but those more frequent visits enable them to get better care and have more people observing them to make sure that when they need hospitalization, they get hospitalization. So, before it's too late, their outcome could be improved. So, there is a lot of benefit in participation in clinical trials.

Natalie Salvatore, MSN, MBA, RN:

Well, thank you so much for taking time to review a little bit of the evolution of research and how we've really grown and expanded the inclusion criteria over the years to include the patients that we see before us. And of course, always the advice to our colleagues on how to speak and educate patients and encourage them to participate in these trials so that we can continue developing treatments to make our patients healthier.

Eileen Hsich, MD:

Well, it's my pleasure. And I hope that we all have a better future because our future depends on the research that we do so that we can advance the field.

Announcer:

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