Ilko Ilev

Zierler:

This is David Zierler, oral historian for the American Institute of Physics. It is June 24, 2020. It is my great pleasure to be here with Dr. Ilko Ilev. Ilko, thank you so much for being with me today.

Ilev:

Sure. It's my pleasure.

Zierler:

All right. So, to start, can you tell me your title and your institutional affiliation?

Ilev:

I'm a Senior Biomedical Research Service Scientist, a so-called SBRS scientist. SBRS Program had been established years ago within the HHS (Health and Human Services) Department including in National Institutes of Health (NIH) and U.S. Food and Drug Administration (FDA). In FDA, SBRS is used to recruit and retain outstanding research and review scientists who are actively engaged in clinical/product research evaluation; or actively engaged in peer?reviewed original biomedical research and who are considered by their peers to be outstanding in either of these activities. Those are scientists with different backgrounds, comprehensive knowledge and extensive expertise that is dedicated to address regulatory science and public health concerns; in my case, in the field of medical device evaluation and public health within FDA’ Center for Devices and Radiological Health (CDRH).

I'm also chairing a research laboratory on Optical Therapeutics and Medical Nanophotonics (OTMN Lab), which is part of the Division of Biomedical Physics at the Office of Science and Engineering Laboratories (OSEL), CDRH, FDA. You've seen probably the Agency structure, in which CDRH is of one of the five centers within FDA. I have been appointed to the SBRS position in 2012. I am with FDA since March 1998, initially as a National Research Council (NRC) Research Associate in CDRH for three years. Later, I was appointed to Staff Fellow, Senior Staff Fellow, and Senior Staff Scientist positions from 2001 to 2012. I can provide additional background information as needed.

Zierler:

Sure. We can develop that as we continue, but let's start going right back to the beginning. Tell me, where were you born? Where are you from?

Ilev:

Originally, I am from Bulgaria, an Eastern European Country. I graduated from Sofia University in 1982 with a B.S. degree in physics and quantum electronics, and a M.S. degree in quantum physics in 1983, and from Technical University of Sofia with a Ph.D. degree in laser physics in 1992.

Zierler:

Are your parents from Bulgaria?

Ilev:

Yes. My parents are Bulgarian, unfortunately, they passed away in the last several years. I still have a sister and family members there in Bulgaria.

Zierler:

What did your parents do for a living? What were their professions?

Ilev:

They were associated with some services in Bulgaria, labor services. My father was very good in math. Probably, I took some of his abilities and loved math and physics.

Zierler:

Now, can you tell me how the Bulgarian educational system works? In other words, when did you commit to physics as a course of study? Was that in high school? Was that until you got to college? How did that work?

Ilev:

We have maybe a slightly different system. I'm here since 1998, so 22 - 23 years, and I don't know about changes recently. But in my time, we used to have actually a similar structural educational system with elementary school and kind of middle school and high school after that. So, I loved at this time all the natural-type sciences, including math and physics. I graduated from a specialized mathematical high school and I was also involved in various math competitions including at national level. We called these competitions Olympics in Mathematics. So, I loved to do that. Probably, this was the time when I began to look, to be challenged and to enjoy of finding original solutions of non-standard and tough problems, and this patient has been projected towards my entire future carrier. And, I decided, okay, I am going to proceed in this direction to the field of physics, along with mathematics that is of course, the language and analytical tools in physics and they were closely related.

Later, in the Sofia University, we had excellent and very dedicated Professors. I graduated in the field of lasers and quantum electronics, in the Faculty of Physics. Actually, my Professors at that time were Ph.D. and Associates in the field of laser physics, most of them graduated from various Russian Scientific Institutions. They were Ph.D. students or postdocs of Professors from the Labs and Institutes of two of the three Nobel Prize Winners for the invention of lasers, Prof. Prokhorov and Prof. Basov, along with Prof. Townes. So, for some reason, I was lucky, to study in the field of laser physics and quantum electronics because the educational and research level in this field, I think, was very high, extremely high and competitive. All my, not only Professors but Assistants and Associates as well, they were very well educated and knowledgeable within this field. And, later when I came here in the US, I said to my colleagues when I saw the fundamental books that I have read during my student years - I knew all those books of quantum electronics in English, of course. But, on the top of this, we knew the books from the other school. So, it was kind of a very effective mixture, a very good combination between the two trends, I would say. Again, not all departments and fields in physics at the Universities were in such a strong advanced position, but, luckily, this field of quantum and laser physics was very well developed.

Zierler:

What was your dissertation on, Ilko?

Ilev:

My dissertation—I'm looking now in my CV. The PhD thesis was titled Novel Lasers with Direct Optical Fiber Output for Nonlinear Conversion of Frequencies in Optical Fibers. The thesis scope was focused on development of alternative effective laser designs with direct lens-free optical fiber outputs and their implementations towards nonlinear broadband frequency conversions in optical fibers. And, again, the University Professors, my Supervisors have established a highly competitive level of requirements for the PhD defense, as in this specific research field, we were required to publish between three and five peer-reviewed papers in Western journals, in well-established journals. Those were very tough requirements, because you can imagine the significant difference of the lab funding between there and here. We had to dedicate extremely strong efforts to cover these requirements.

Zierler:

And how good were the labs that you had to work with as a graduate student?

Ilev:

Our Professors and Supervisors were familiar and knew the basic equipment requirements for this class of laser labs since they have collaborated and visited distinguished labs in many European countries such as Germany, France, UK. And, they tried to equip our labs at least with the basic critical equipment, and with some good ideas, actually, we managed to cover all these requirements and to be competitive. For instance, my PhD research thesis was based on one of these new ideas of how to couple laser emission directly from the laser resonator to optical fibers without any focusing elements using so-called optical tapers or optical funnels, whose input serves as a direct output component of the laser resonator. So, we published competitive papers in well-recognized peer-reviewed journals, and I also managed to provide an effective defense of the PhD thesis.

Another example that I remember from one of my Professors, when they invited a Nobel Prize Winner from USA to visit the lab, a very distinguished scientist in the field of nonlinear optics. He came to the lab and he liked some of the equipment and some of the ideas employed. At that time, a dye laser was operating in the lab with no proper commercial pump to circulate the dye through the laser cavity. Instead, a system with two bottles with the dye medium at an upper and a lower level was used. The reaction was "Oh, I like this idea” (laughter). Every 30 minutes, the bottle levels needed to be exchanged, which provided a continuous circulation of the dye through the laser cavity. So, those are just some examples how we worked at the time of no completely sufficient equipment in the labs. Later, I have had a great opportunity to work in very high-level labs around the world, including in the Institute RIKEN, Tokyo, Japan I can describe this interesting story in more details. This was one on the most advanced and well-equipped Institutes that I have had a change to work, so I can make a difference between what we had in Sofia University and Tokyo, Japan.

Zierler:

So please tell me that story.

Ilev:

Oh, yeah. After finishing my PhD term, I continued to work as a Senior Assistant Professor in the Technical University of Sofia, at the Department of Applied Physics, teaching courses on general physics and some specialized courses on quantum electronics and fiber optics. At that time, my applications to work as a visiting scientist in some well-known research institutions have been accepted. Initially, I had a great opportunity to work in the labs of Prof. Brian Culshaw at the Strathclyde University, Glasgow, UK, who is one of the most recognized scientists worldwide in the field of fiber-optic based sensors and a former President of the International Society for Optics and Photonics (SPIE). I was so happy to be able to work in these advanced labs, generating a number of peer-reviewed studies and papers for a relatively short of period of time employing some good ideas. And, after this period of time, I was accepted as a visiting scientist in the institute, RIKEN. This is the Japanese name of this institute in Tokyo, Japan, whose full name is the Institute of Physical and Chemical Research. I worked in the RIKEN laser labs. Initially, when I went there, I was so impressed by the level of the research and equipment that I would be able to work with, even not comparing with the Sofia University, but even to compare with the University of Strathclyde in Glasgow. So, it was an amazingly well-equipped lab. At that time, I had a great chance first time to work with ultrafast femtosecond lasers, and I continue now in FDA to perform research on ultrafast pico- and femtosecond laser applications in medicine.

Zierler:

What was special about working with this new class of lasers?

Ilev:

This new class of lasers are amazing since they provide unique, incomparable with other lasers properties such as ultrashort pulses with pulse duration between 10^-12 to 10^-15 s. Because of the ultrashort pulses, these lasers provide a minimum amount of energy in the picojoule to microjoule range, which is very attractive for biomedical applications. At the same time, the peak power is extremely high, in the range of terawatts, which is because the pulse energy is compressed in a very short femtosecond pulse duration. This feature is unique, because these extremely high levels of peak powers and laser irradiances or intensities provide the best conditions for generating and investigating nonlinear effects in various non-organic and organic materials with a vast range of applications. It was amazing because I studied different types of nonlinear effects caused by these lasers, and almost all materials, nonorganic, organic even my shirts, everything generated fluorescence and nonlinear effects because of this high peak powers.

Zierler:

Mm-hmm.

Ilev:

I was so impressed by this type of advanced lasers. It was a pivotal point, a very crucial point for me, as well, for my career. I spent between 1995 and 1997 plus a few months, in the institute RIKEN and observed how the biomedical field is growing there. During the time of my stay, RIKEN built up two new buildings with new directions and advanced application in the field of brain research. I saw how my Japanese and International colleagues, excellent scientists with a background in varies areas, such as physics, chemistry, imaging, sensing, spectroscopy, they switched to employ their comprehensive knowledge and extensive experience to the biomedical field.

Zierler:

Why did they switch, Ilko?

Ilev:

Because this is a very impactful and attractive field, the life science and biomedical application field. These scientists realized that with their knowledge and experience, they very successfully can solve some of the critical problems in biology such as using advanced spectroscopy, imaging or sensing based techniques. They said, okay, I can do that. I have done this for different types of media or materials. Since the biomedical field is very challenging, requiring high sensitivity and enhanced repeatability, I saw how all these people—I was so impressed, all these colleagues, Japanese, and not only Japanese, because this was international center and I worked with people from all over the world, they're extremely interested and challenged to focus their expertise to the field of biomedicine. This was a turning point for myself as well, I said, at this time, okay, it's very impressive to be able to contribute to the biomedical field. I did some research, actually, when I worked at Strathclyde University in the area of biomedical sensing. I continued to further establish my interest and contribute to the biomedical field in the institute RIKEN. Since this time, I applied for a postdoctoral position at the U.S. Food and Drug Administration (FDA). My application was successfully accepted by the American Academy of Science/National Research Council (NRC) to work in the Center for Devices and Radiological Health (CDRH) at FDA, with one of the well-recognized scientists in FDA, Dr. Ronald Waynant. I came to FDA in 1998 to fulfill my desire to work in the field of biomedical research.

Zierler:

Ilko, how did you first hear about the FDA from the other side of the world? How did you know that the FDA would be a place that would be a good place for you to do your postdoc?

Ilev:

It's a good question. I'd heard about FDA while I worked in the institute RIKEN in Tokyo, Japan. Some of my colleagues said that all our research in the biomedical field should be synchronized with the safety and efficacy requirements of an agency, a similar to FDA agency in Japan, but first time I've heard this, ironically, in Japan about the FDA. I found that FDA announced though NRC, some postdoctoral research associate positions and I applied, and I was happy to be able to work with Dr. [Kristopher] Waynant. It is interesting that my Japanese colleagues knew Dr. Waynant and were familiar with his previous work in the field of lasers and applications from the time when he worked in the Naval Research Lab. It’s another interesting story—because Dr. Waynant had a background in electrical engineering, quantum electronics, and lasers, he has generated one of the first UV laser radiation. My Japanese colleagues worked in a similar field and they said, wow, you are a very lucky man. You will be able to work with Dr. Waynant at the FDA. And he, for the same reasons later, when I discussed with Ron, he said, "This was the reason I decided to switch also to biomedical field, to realize my potential and knowledge from other areas to this field."

Zierler:

Ilko, in what ways were you able to transform your studies at FDA as an NRC postdoctoral research associate from your graduate student experience and interests into biomedical physics?

Ilev:

Okay. During my career, I have been always interested and felt very comfortable working with various classes of lasers, fiber optics, sensing, imaging and spectroscopy modalities for various applications. My initial interest in the field of biomedical physics started even during my PhD years, I had a portion of my thesis focused on some sensing approaches, including biomedical sensing, so I had this thought about specific biomedical applications. Later, when I went to Strathclyde University, I continued to work in this direction of attractive biomedical applications. My definitive decision and primary interest into biomedical field I defined when I was, as I previously mentioned, at the institute RIKEN, seeing all this transformation of great scientists with a similar background switching and trying to help to biomedical field. So, this was a kind of a gradual transition for myself. Of course, my strong dedication to this field including to very challenging and attractive unresolved issues was when I started my postdoctoral study at FDA with Dr. Waynant. I enjoyed working in this field. Employing all my background and experience in the areas of imaging, sensing, and spectroscopy, it was relatively very easy, to transfer this knowledge into the biomedical field.

To illustrate how extensive is the field of biomedical applications using optical and laser techniques, I would like just to add some additional thoughts on this topic. Currently, I'm editing a number of high impact factor journals including serving as a Primary Editor for Biophotonics and Nanobiophotonics of the IEEE Journal of Selected Topics in Quantum Electronics journal. As one of the JSTQE topics is biophotonics, I have also served also as Chair of Biophotonics Committee of the IEEE Lasers and Electro-Optics Society (LEOS), and IEEE Photonics Society (PS). Due to the significant interest in photonics areas of developments and applications including biophotonics, the former LEOS Society has been renamed to PS Society and we have defined the broad field of biophotonics exactly as a cross-sectional and integrating field between the areas of photonics, including lasers, optics, fiber optics, spectroscopy imaging, integrated with the areas of biology, biomedical and health science. As a result, this synergy between the photonics and biomedical areas lead to the establishment of the biophotonics field. So, probably something similar has happened to my career as well. I have found an effective cross-section between my previous comprehensive experience in the photonics areas with knowledge and expertise in the biomedical and health science areas to contribute to the biophotonics field. In addition to biophotonics, an additional filed of nanobiophotonics has been defined in cases when our studies and considerations are limited to targets and objects with sizes smaller than 100 nm. I have been also involved in the nanobiophotonics field through multiple research projects in my Lab, editing journals, and chairing conferences focused on advanced developments in nanobiophotonics.

Zierler:

Ilko, did you have any idea as a postdoc that you would make a life for yourself in the United States and a career at the FDA, or did you think you were going to go back home afterwards?

Ilev:

That is a good question. The initial intention actually was to spend two or three years as a postdoc here. However, because of the successful and very productive 3-year postdoctoral term at FDA/CDRH under the American Academy of Science/National Research Council (NRC), NRC has organized a final outcome session at FDA/CDRH, at which I have presented an extended summary of the major results and accomplishments achieved during the NRC term. I have received strong support and an offer to continue working in the biophotonics and nanobiophotonics field in FDA/CDRH FDA. I have enjoyed working and having a productive time here in FDA, as it was the case before that in RIKEN, Japan. In RIKEN, we published about 30 peer-reviewed papers for two-and-a-half years, and also for the three years spending in FDA with Dr. Waynant, we have published multiple peer-reviewed studies. It’s interesting, some of these studies have been published in highly respected journals that are related probably to your institution, such as Applied Physics Letters. Those are relatively short, letter-size papers, but we were happy to publish in this competitive and highly impactful journal. So, answering your question above, initially I didn't plan to do that, to stay for a longer period of time, but seeing all the conditions and capabilities in the labs, all the support that I got, and the fact that when you have interesting ideas, and you can realize these ideas pretty quickly, and the overall productivity is, again, very rewarding. And, I was happy with the opportunity to be able to continue working on these ideas.

Zierler:

Did you stay in the same lab when you converted to full time after your postdoc?

Ilev:

Yes, absolutely. It is very interesting that I have been working in the same Agency/Center/Office/Division and Lab from day 1 to this moment for over 22 years. As I previously mentioned, in 2007 we moved from the previous FDA/CDRH location at Rockville, MD, to the FDA headquarters now at White Oak in Silver Spring, MD. At previous location in Rockville, we didn’t have the best conditions for precise studies. The building was shaking, and we had to work after 10:00 p.m. during quiet time, to be able to perform some very precise imaging and sensing experiments. However, since 2007, we have been asked to design some of the new labs at White Oak, the laser-related labs in the FDA, and to establish multifunctional, vibration-isolated and state-of-the-art type labs. We have received a strong support for these labs in the new buildings at the FDA. In 2008, we established one of these labs as focused of studies in the field of optical therapeutics and medical nanophotonics (OTMN Lab), and we have been working in OTMN Lab in this field since that time.

Zierler:

The FDA, of course, has the mission on ensuring patient safety, both in terms of regulation and optimization of devices. So, I'm curious how your work plays into that overall mission.

Ilev:

Yes, that is correct. Our regulatory research in FDA/CDRH is motivated by the unmet needs to address major regulatory and public health safety and efficacy concerns and challenges. In addressing these challenges, we have developed innovative test methodologies, test protocols and phantoms, and analytical models for evaluating safety and efficacy of the emerging diagnostics and therapeutics devices. The key results and outputs of these studies are correlated to the patient reported outcomes in order to better predict the device properties and their effects on the device safety and efficacy, and therefore, on the patient health quality. Moreover, our contribution to the FDA/CDRH mission includes also reviewing device applications to FDA/CDRH. As regulatory scientists, we are involved and about 30% of our work is dedicated to providing expert reviews on medical devices. In many cases, the safety and efficacy evaluation of these devices are related to the patient feedback and reports. For instance, I have performed reviews of laser and optical radiation safety issues that a medical device with specific intension use might have. In many cases, these issues are associated and affect the patient safety by avoiding any tissue-damaging effects.

In addition, I serve as a CDRH Laser Safety Officer (LSO) and a Co-Chair of the FDA Laser Safety Committee, and thus, those are another significant responsibilities that I'm having, to evaluate and establish safe conditions in the laser labs, and to provide laser radiation safety training to associates and fellows working in these labs. Furthermore, we have been working recently on defining and establishing new research programs in OSEL/CDRH, which are also related to the patient's reports and feedbacks. I'll give you one example from the OTMN Lab, in which a well-defined research program is focused on evaluating intraocular lens (IOL) implants. Those are IOL implants used in cataract surgery to replace the crystalline lens with an IOL. Although, this is the most commonly performed surgery in the United States and in the world, even if we have a small percentage of unsuccessful surgery or surgery with some safety concerns and issues, we have to test and to evaluate these cases. To address these regulatory and public health concerns, we developed a series of novel test methodologies for complete quantitative evaluation of critical IOL characteristics. As a part of the IOL evaluation process, we have collaborated with the Wilmer Eye Institute at Johns Hopkins University. We are in the process of getting extracted samples of IOLs from patients with complaints, and we're going to test these IOLs and to figure out what actually is the issue that we're having for the patients with this particular unsuccessful surgery, or surgery with safety concerns. So, this is one example of how our regulatory research can be directly related to the patients' feedback and reports.

Zierler:

Ilko, how closely do you work with device manufacturers?

Ilev:

That is also an important question. As we have been working to protect and promote Public Health, we have been encouraged especially during the recent years to collaborate with the Providers of medical devices on addressing the existing major concerns and challenges related to device safety and efficacy. Since we're a regulating Agency, we should sign some form of cooperative agreement with these companies. In general, it’s a very effective collaboration process since we are working jointly with the Provider of a specific device. For example, I am in the process now of establishing such an agreement with companies working in the field of photo-biomodulation because we're getting directly feedback from them regarding the main issues they experience in providing and manufacturing these types of devices. And also, they're getting feedback from us about the critical requirements and the safety and efficacy issues that they might have. So, I think, these collaborations with Providers under cooperative agreements are very productive and of mutual interest.

Zierler:

And what about medical professionals themselves, do you ever work with doctors or other clinical providers?

Ilev:

Yes.

Zierler:

—who raise issues or concerns that are relevant to your office and what you do?

Ilev:

Absolutely. I'm doing this through different ways. I'm an elected Fellow of several major professional societies such as the Institute of Electrical and Electronics Engineers (IEEE), the Optical Society of America (OSA), the International Society for Optics and Photonics (SPIE), the American Institute for Medical and Biological Engineering (AIMBE), and the American Society for Laser Medicine and Surgery (ASLMS). I am very involved in various activities of these Societies chairing conferences and editing journals. For example, I serve as a Program Chair of the premier OSA Conference on Electroptics and Lasers (CLEO). This year, we actually held the CLEO’2020 Annual Conference 100% online back in May. Within this conference, we have a comprehensive subconference focused on Biomedical Applications. We have been encouraging the Committee Chairs of these subconference to invite speakers and participants among medical doctors and industrial providers of emerging medical technologies and devices. Since we have identified major gaps in the regulatory science or in the manufacturing field, and we're trying to attract scientists or medical professionals to work on addressing these gaps or to work jointly to address these gaps. In addition, I am also chairing an OSA Technical Group on Photobiomodulation Therapeutics (PBMT), which is another avenue that can be used to combine efforts with medical professionals, companies, distinguished scientists in the field of lasers and biomedical optics to work jointly on addressing these issues.

Zierler:

Does your office ever work directly with patients or with patient advocacy groups who are concerned about device safety?

Ilev:

Yes. Again, we're encouraged to work towards this direction of patient’s outcomes and feedback, like in the project on IOL implant evaluation that I mentioned above. We have been encouraged to correlate and adjust our results and database to the patients' reports and to the real issues. I have colleagues that work also in the field of ophthalmology for retinal imaging, and they are performing some clinical imaging of patients' retinal tissue, again, for the purpose of safety and efficacy.

Zierler:

Ilko, you've given a really good sense of the kinds of issues that come to your office. I wonder if you can talk about what you do with that information. In other words, say a device manufacturer or somebody from the medical community will bring an issue to you. You study that issue, you study the data, you do what it is that you do. What do you then do with that information as it goes through the policy process at the FDA? Can you explain that process a little bit?

Ilev:

Oh, sure. I think, I'm long time enough to be able to speak about this issue in FDA/CDRH. We have, again, several ways to distribute the major results of our regulatory research to the public health and the manufacturers. Like, again, in the case of intraocular lens (IOL) implants evaluation, it was a very productive-type project. We have published multiple peer-reviewed papers in high ranked journals and some of these papers published in clinical journals. The manufacturers and other related groups working in the IOL field, can go and see our vision on the alternative precise test methodologies developed. In addition, we have filed, and multiple patents have been issued on these test technologies. This is another potential avenue. Previously, NIH was responsible for the patent processing, but now FDA has an Office of Technology Transfer and they're communicating with specific companies that might be interested in these types of inventions for licensing. Another way that has been recently established is related to the Medical Device Development Tools (MDDT) program in FDA/CDRH. Those are tools developed in FDA/CDRH for safety and efficacy evaluation of medical technologies and devices. There is a mechanism for publicizing these MDDT test methodologies as they will be available to all the medical device providers. In addition, this is the way how we can communicate and collaborate with a company. Another avenue is based on our work and contribution to international standards. All these test methodologies that we have developed, such as in OTMN Lab, can be adopted and published in the current and future standards as test tools to solve specific problems of manufacturers or people working in this field. Moreover, another avenue is by generating guidance documents in the FDA. When we integrate all this comprehensive database generated by peer-reviewed papers, patterns, we can generate guidance documents on a specific issue which is of regulatory and public health concern for manufacturers. These guidance documents include the critical requirements that FDA has for specific type devices. When the companies are coming to apply to FDA approval, they will have this guidance document with a list with specific requirements the company are going to address before to come to FDA.

Zierler:

Ilko, I wonder if you can talk a little bit about some of the tensions that must come up between the FDA and medical device manufacturers? In other words, companies can spend a great deal of money developing a product, right?

Ilev:

Uh-huh.

Zierler:

And they'll bring it to FDA and then you find that there's some problem with it.

Ilev:

Yes.

Zierler:

Now, naturally, the device manufacturer, on the one hand, it wants to do things right because it doesn't want to get in trouble with the FDA and it wants to make devices that are safe for patients. But I imagine there must sometimes be tensions in terms of how costly this is going to have to be for the company to retrofit some of these devices. So, can you explain the back and forth of how these tensions play out and what have been some of the most productive ways of resolving these differences?

Ilev:

I'm pretty sure my colleagues from the regulatory offices, they can speak in more detail on these issues. But, from my experience working also on the device review processes, I can say that, yes, we have similar cases that you're talking about. And I think FDA has good mechanisms of avoiding these types of cases, like we have so-called preapplication meetings with the companies, pre-meetings. The company can come to FDA with the idea of applying for specific device. I believe this is for free, these type of pre-meetings for the company. They are coming with some preliminary results; FDA is considering very seriously these types of applications. We're establishing a team of reviewers with different backgrounds. Like, in my case, from the laser and optical radiation safety perspective or statistician or people working on clinical issues, etc. So, we're reviewing this device and the review process is scheduled like the real application with the specific deadlines. When we're ready with the review, we're having a face-to-face meeting or tele-meetings with the company, and we're presenting our reviews saying, okay, here are our potential safety and efficacy issues that we have with this device. We recommend these issues to be addressed. When the company actually will come to real application, they're working on these issues to resolve and they are in a much better shape. Many companies, they consider this very seriously and they are coming to these pre-meetings almost 100% ready. They are just making some final touches to the application. But we're having cases with companies when they're considering this pre-meeting as a completely informative process, which is very ineffective. They are coming to FDA almost unprepared, and this is waste of time for both sides. We can say, okay, you have major issues with all aspects of the device application, for instance, with the animal and clinical studies, with the safety evaluation, etc.

So, I have been involved in both cases, when the companies are coming so well prepared and they have a quick approval process after that. And, on the other hand, we're having companies coming completely unprepared. And, again, as a scientist—and I believe, this is the case with my colleagues' work as well—to put and to stay behind a solid scientific background and evidence in reviewing and evaluating medical technologies and devices. In these cases, yeah, we're very helpful to the companies. Even if we have had, in other cases, the company spending a huge amount, for example, for clinical studies, we have such a policy of less burdensome policy in FDA when we try really—we always try to help the company to minimize, for example, the clinical studies required but not compromising device safety and efficacy. I think. what I'm seeing is complete good intention of my colleagues of FDA attempts to help to the company to resolve the issues.

Zierler:

Ilko, I'm curious, much of the work resolves around issues coming to your office. Does your office have a component where you're actively going out into the field or working with your partners in industry or other agencies so that you are not passively accepting information to work with but you're actively going out and discovering things that need to be dealt with?

Ilev:

That's also a very good question. In our Office of Science and Engineering Labs (OSEL), we have practiced to test so-called regulatory samples in some questionable and more complex cases. One way to do this is to test samples before the review process. Based on these tests, we can say, okay, you have these issues that are recommended to be addressed. However, we are not doing these tests on a regular base, because otherwise my lab and the labs in FDA will be converted in testing labs. All the companies will send samples to us for testing, so we're not doing this. Concerning field support inspections, FDA/CDRH has performed such inspections, however, this responsibility is associated with the regulatory office OPEQ, Office of Product Evaluation and Quality. In the area of radiological health including laser and optical radiation safety, one of OPEQ’s offices on In-Vitro Diagnostics and Radiological Health (OIR) performs some of the onsite safety inspections. One of my former PhD grad-students completed very successfully his PhD on femtosecond lasers in my lab a few years ago. Now, he is a very talented and productive scientist in CDRH/OPEQ/OIR, and he has performed some of the onsite safety inspections related to laser and optical radiation safety. In addition, FDA/CDRH has field support Labs at various locations and they are performing in-situ testing and visits as well.

Zierler:

Ilko, what are some of the most important collaborating agencies within the federal system that your office relies on to do its work?

Ilev:

From federal agencies and institutions within the Department of Health and Human Services (HHS), this is undoubtedly NIH, National Institutes of Health. We have collaborated with various NIH divisions on topics of mutual interest related to Public Health. However, since we are both federal agency/institution within HHS, we cannot directly apply for NIH grant support, but we can apply jointly with Universities. For instance, the FDA/CDRH OTMN Lab has been involved recently in a collaborative NIH granted project with Tufts and Cornell Universities, and University of Texas at Austin, on two-photon imaging for early cancer diagnostics. Outside HHS, the FDA/CDRH OTMN Lab has a long-time and productive collaboration with Uniformed Service University of the Health Sciences (USUHS). This over 20-year collaboration has led to the establishment of the new field of Photobiomodulation Therapeutics (PBMT), which is a rapidly expanding topic towards a broad range of emerging PBMT applications.

Zierler:

Ilko, I'm curious, as an immigrant, you have a broader perspective, perhaps, on the impact of your work, not just within the Unites States, but globally. I'm curious if you see the impact of your work going beyond the United States. In other words, the FDA, of course, is part of the US Federal Government, and its regulatory affairs are most relevant—

Ilev:

Yes.

Zierler:

—in the United States. But have you followed where your office and its research might have influenced both science and regulatory issues beyond the United States?

Ilev:

The regulatory research projects in FDA/CDRH are focused on protecting and promoting Public Health through the development and implementation of advanced test methodologies and tools for addressing major regulatory and public health concerns and gaps in evaluating safety and efficacy of emerging medical devices and products. However, the regulatory research accomplishments have a significantly broader impact since the test methodologies and tools developed are extensively publicized and accessible worldwide via: peer-review publications in highly ranked and well-recognized international journals; reports at major national and international conferences; and additions to national and international standards. Thus, these developments include advanced test approaches, protocols, phantoms and analytical models that are accessible and can be employed by any labs and institutions worldwide in evaluating new and emerging biomedical technologies and medical products.

Furthermore, the broader impact of these developments is further enhanced by our activities within major professional societies. For instance, I'm involved in many professional societies through various activities including organizing and chairing conferences, topical meetings and committees as well as editing major journals in the broader areas of biophotonics, nanobiophotonics, biomedical optics and biomedical engineering. As mentioned above, I have been elected as a Fellow of a number of these major societies such as IEEE, OSA, SPIE, AIMBE, and ASLMS. I have been also invited to present Plenary, Keynote, and Invited Talks at National and International Conferences organized by these societies on cutting edge topics including advanced developments accomplished in our Labs. This is considered also as an additional great opportunity to present and deliver our key studies and results to a broader audience. Of course, in such cases of invited talks as well as any peer-review publications, abstracts and proceedings, we should follow well-established publication clearance procedures here in FDA which are potentially related to any sensitive regulatory issues. We follow these procedures however, our talks and publications are focused basically on the scientific aspects of the research studies, on the approaches employed for solving specific regulatory issues and challenges purely scientifically. Since these approaches are accessible and can be adopted in many labs and institutions worldwide, I believe, our research is well-recognized and respected.

Zierler:

What are some limitations that you see that prevent you from doing the best work that you can possibly do, both in terms of bureaucracy or funding or issues with communication? What are some of the greatest challenges that stand between the responsibilities you have and the purest and most efficient way to achieve those objectives?

Ilev:

A great question, as well. I will start probably from the challenges. I think, I am long enough time working in this regulatory Agency to realize the importance and challenges of this work. Although, I had the choice before to come to FDA, either to continue as a professorship in University somewhere in the States or other places, I decided to come here because it's a highly respected and very challenging area of regulatory and public health related work. As we're working to evaluate safety and efficacy of real emerging medical devices and biomedical products, we're at the end of the road before this device or product to go to clinic. Thus, after the Agency approval or clearance, the device is going to clinic, and this device should be safe and effective, and therefore, we don't have a choice for failure. Because of this, it has been very challenging and interesting for me to work here.

It has been my belief progressively from the very beginning, and this is what I am saying to my colleagues especially newcomers, that the most winning strategy is to identify real issues, unresolved major issues and gaps in the regulatory science, devices and products, and to develop and implement advanced tools and methodologies to address these issues along with publicizing these tools and approaches in highly impactful journals and conferences getting constructive feedback and assessment on the level of these developments. In this way, closing this loop between the research need, tools development, addressing the need, and publicizing of approaches, you will be happy with the results and this win-win situation, when the problem will be solved, and you personally will be happy with the accomplishments.

In addition, a key element of this strategy is that it includes very productive and enjoyable collaboration efforts and projects with your knowledgeable colleagues as well as distinguished expects form outside institutions such as Universities, Government Labs, and Industry. For instance, I have been collaborating during all these years on various research projects focused on major unresolved gaps with my colleagues from regulatory offices. They are extremely experienced reviewing medical devices including major safety and efficacy concerns for decades. Having these colleagues on the research team, it creates an inspiring atmosphere for identifying and traying to address real issues. They would say, okay, I see and know that this is a very serious issue for that type of devices for a long time, and it needs to be resolved. At this point, based on our expertise and knowledge, we employ advanced approaches to solving this problem. As an additional benefit, during the entire process focused on addressing unresolved regulatory and public health needs, any potentially existing bureaucracy issues (if they would exist at all) would be meaningless and with negligible effects in such cases. You enjoy doing that, having the problem, solving the issues, publishing results at a high level. And, yeah, this is what I enjoy doing.

Zierler:

So, let me ask the same question but flip it.

Ilev:

Okay.

Zierler:

In what ways does the FDA give you the tools that you need to do the job that you're required to do?

Ilev:

As a regulatory federal government agency, FDA is an interesting institution for science. The regulatory process of reviewing safety and efficacy of medical devices and products is based on science and scientific evidence and data. At the same time, people are generally thinking in two ways for FDA science: they're saying either, oh, they're a Federal Agency, they have all the resources that they ask and need. The other group are saying, no, FDA, doesn't do any science. And the truth is always in the middle or somewhere. Regarding science funding in FDA, we have experienced some restrictions for applying for grants directly with other government institutions like NIH, we are sister organizations with NIH within HHS Department. The same is for NSF, National Science Foundation. However, we can jointly apply for these grants through collaboration projects with a third party like a University. For example, as I mentioned above, the FDA/CDRH OTMN Lab is involved in a recently granted collaboration project with Tufts University, Cornell University and University of Texas at Austin supported by an NIH/NIBIB BRG Program. Within FDA, answering your question, we have some intramural funding under various initiatives such as Critical Path, Office of Chief Science, Nanotechnology, etc. These intramural grants are not very large, but they provide basic support for supplies, some equipment and fellow students to keep the projects running and we're happy with these grants, as well. The intramural grants are especially helpful for providing support for fellow students for working full-time in the labs usually for a one-year period of time under the ORISE Research Program used for managing students and fellows under these grants.

Zierler:

Ilko, what are some of the most satisfying successes you've experienced over the course of your career at FDA?

Ilev:

Yeah. I think I mentioned it, that is the enjoyable and effective time that I have been working on real biomedical device and products having unresolved safety and efficacy concerns. Because, before this, I worked in Academia or various scientific institutions worldwide where you can do science, you can do research, you can publish results, but those results can be either completely applicable, partially applicable or not applicable to clinical technologies and devices. In the case of FDA, as I mentioned, we are reviewing real biomedical devices and products developed for clinical use. After the FDA positive decision and approval, these devices are going to clinic. So, you have to be completely convinced that these devices satisfy the safety and efficacy requirements before clinical implementation. And, these are the satisfying successes that we are experiencing and enjoying. In many cases, some of the major devise concerns are associated with issues related to physical principles, to engineering, or specific issues related to biomedical optics or lasers. Employing your knowledge and expertise in these areas, you are glad to be able to contribute towards complete and successful evaluation of the subject device including defining specific deficiencies and recommendations for improving the performance and safety, or for solving particular problems. If the problem represents a major existing gap and research challenge, we involve regulatory research studies focused on resolving this gap through development and implementation of advanced research approaches in the Labs. We publish these peer-reviewed studies, present the main results at various topical meetings, and file invention reports and patents. All these accomplishments represent another form of satisfying success. So, I think, I found a great place for me to enjoy (laughter).

Zierler:

Ilko, from your education, you're really a physicist. That's the world that you come from.

Ilev:

Yes, yes.

Zierler:

I'm curious if you can talk about, what are some laws in physics or concepts in physics that are most important for the work that you do?

Ilev:

I have many examples of ideas or laws or areas coming from physics directly applicable to my work. For instance, right now, we're approaching an attractive field in physics related to Raman spectroscopy, which is a very powerful tool to investigate and understand at a molecular level the signature signals coming from specific process and biomarkers in biophotonics and nanobio-photonics. Raman spectroscopy methods have been developed and used extensively for more than 90 years; the Nobel Prize in Physics on Raman spectroscopy was awarded in 1930. In our Labs, using label-free, fingerprint, highly sensitive Raman spectroscopy approaches, we have been working on the development of advanced test methodologies and tools for studying and identifying dominant mechanisms of light-tissue interactions and intrinsic biomarkers associated with safety and efficacy of emerging Photobiomodulation Therapeutics (PBMT) devices and technologies. This is a critical research and regulatory gap of incompletely known dominant mechanisms of action of these PBMT devices. Multiple clinical studies and data on a broad range of PBMT applications have been presented and published in recent years. Some of the PBMT device applications have been approved based on provided clinical evidence and data. However, the clinical data—answering also to one of your previous questions, are associated with some burdensome type studies that we're trying to minimize. If the dominant mechanism of action for these specific devices and for specific diseases, is well defined, we can optimize key characteristics of the PBMT device including critical parameters of the laser and optical sources and biomarkers related to the device safety and efficacy. Some of these biomarkers are associated with cellular generation of specific reactive oxygen species (ROS) that can be detected and quantified using fingerprint Raman spectroscopy techniques. That, I think, is a great example of how a powerful Raman spectroscopy-based tool coming from the field of physics can be effectively employed as a label-free fingerprint sensing modality for resolving a complex mechanistic issue in biophotonics.

Another similar example is related to application of infrared (IR) spectroscopy that is also a signature sensing technique coming from physics. Based on this technique, we have developed and implemented a series of high-resolution, non-contact, real time and fingerprint sensing modalities for applications focused on detecting and identifying various biological and chemical contaminations on medical device surfaces, or for mechanistic investigation of some therapeutic devices. I could provide many other examples of tools and ideas coming from the field of physics to applications in biophotonics and nanobiophotonics. I would like to mention just one additional example from my research carrier, which is related to the use of confocal microcopy as a powerful imaging and sensing tool coming from physics for solving a major existing gap for precise evaluation the dioptric power of intraocular lens (IOL) implants. Employing fiber-optic confocal microscopy approaches, I have developed a series of innovative patented and extensively published technologies for multifunctional, high-resolution and objective evaluation of IOL dioptric power characteristics. Those are powerful confocal microscopy techniques with sub-micron and nanometric resolution.

Zierler:

Ilko, over your long career at FDA, of course, the challenge is, as you get promoted up the managerial ranks, how do you remain a scientist? How do you remain connected with the science? I'm curious if you can share any tricks and tools of the trade you've learned to enjoy both those promotions and to deal with the increased responsibility, but still remain engaged in the day-to-day science that is the core of your—on your job?

Ilev:

Yeah. You prepared very good questions! (Laughter) I was thinking, actually before to be assigned to this SBRS (Senior Biomedical Research Service) position, okay, maybe it's time now to try with all my experience to switch to a more managing-type position on the top of chairing an FDA/CDRH Lab, although I knew I will go away partially from science eventually with this position. Fortunately, at this time about 10 years ago, I had a discussion with a very smart and highly experienced office management colleague. He came to my office and said, "Ilko, forget this managing type of career. Go ahead and proceed with this very brilliant type of SBRS position and you will enjoy it. I know that you enjoy doing science rather than to go to management-type career." And, I'm very thankful to this moment, actually, I said to myself, OK, I have a managing responsibility now within the research lab, but this is not like a complete management-type activity. And indeed, I have been happy and enjoyed this dual responsibility status.

Zierler:

(Laughter) Well, Ilko, you've provided such a wonderful overview of how things work at the FDA, which is exactly what this is all about. I think, for my last question, I want to ask you something that's sort of more forward-looking, and it applies both to your career and your office as a whole, and that is: What are you excited about in the future in terms of new technological advances, new regulatory mechanisms, new ways of building relationships with your many partners? What are you excited about achieving in the rest of your career, both personally and as a member of your larger office?

Ilev:

Okay, it’s also a very good question. I've seen, during all these years of my carrier, new and emerging technologies coming to FDA on a regular basis. So, it's not a surprise for me now that we see new technologies and devices coming, like last year we had a company coming to FDA with a completely new type device. Nobody actually had experience on these types of devices, combining femtosecond therapeutic lasers with some specific applications to do in-situ corrections of some implants. And, again, this is what I am saying to my colleagues, to my especially younger colleagues and fellows working in the Lab, "You should work very hard and constantly improve your knowledge and expertise in order to be prepared for this type of moments, when you see new technology coming and requiring a comprehensive evaluation. You have to prepare yourself though performing advanced studies, publishing your peer-reviewed papers, attending and presenting at major conferences, writing reports and guidelines, working and cooperating with distinguished scientists." Any of these components are required and contribute towards the development of yourself as a knowledgeable and experienced expert in specific field, and to be well-prepared for the coming new technologies and devices. Even today, this morning, I had to respond to one message coming from other offices. They said, "Oh, Ilko, do you remember a few years ago we had a case of a very determined company coming to FDA with some unsupported claims?" And, again, you have to be able to address these issues on an urgent matter using science-based evidence. You have to be an expert in this field, to be able to help and to protect FDA and public health for this.

Furthermore, I'm seeing different types of new fields coming, new technology like nanotechnologies now coming to FDA, or combined devices, drug and devices. I have been more and more involved recently with this type of combined devices, working with other centers in FDA like Center for Drug or Center for Biology. I have been involved in similar to COVID-19 studies on decontamination of different types of surfaces or targets using UV light. And, again, you have to be prepared for these moments, to provide a comprehensive review or to address these issues on an urgent matter, because it happens very frequently. New technologies are coming to FDA, they are coming to your lab, and they're saying, OK, you have a short period of time to provide a review or data just to approve or not to approve this technology. How feasible is this technology, or not feasible to this application? I used to have this type of urgent cases requesting to perform some initial studies to confirm or not to confirm the efficacy of this technology. All clinically relevant equipment has been provided to the Lab for about a week. We performed this study and we concluded that this type of technology is of safety concern, so it needs additional evidences. So, that is just one example for the critical need of our development and preparedness in order to be able to address complex and urgent requests for evaluation of new and emerging devices and products coming to FDA and public health.

Zierler:

Sounds like there's much work to be done, and much to be excited about.

Ilev:

Yes, absolutely, David.

Zierler:

Ilko, it's been such a pleasure talking with you today. Thank you so much for sharing your insights and perspective with me.

Ilev:

Sure. Thank you, David. Any further questions or information that you need, I will be pleased to address and provide.

Zierler:

Okay.