20Q: Ototoxicity and Audiology - Insights from an Innovator

From the Desk of Gus Mueller

Ototoxicity and otoprotective agents. Related topics that probably don’t come up too often for the average audiologist, but when they do, you certainly want a good source for reliable information. We thought that we could help you out here at 20Q. Of course, our Question Man needed an expert on the topic, and that was the easy part—we selected the same person that you all would have picked too: Dr. Kathleen Campbell of Southern Illinois University.  Because Dr. Campbell has devoted her career to this unique aspect of audiology and hearing science, we also asked her to give us a little background regarding the path she has taken.

Kathleen Campbell, Ph.D., is Distinguished Scholar and Research Professor at Southern Illinois University (SIU) School of Medicine, Department of Medical Microbiology, Immunology and Cell Biology. Her research contributions over the years are exemplary. She has received over 60 grants from National Institutes of Health, US Department of Defense and other agencies for her research on otoprotective agents. She is the sole inventor for the protective agent D-methionine patents, and has received 5 US and 33 foreign patents for her inventions for pharmacologic otoprotective agents. She is the author of Pharmacology and Ototoxicity for Audiologists.

Dr. Campbell is a Fellow of the ASHA and has received the Honors of this Association. She also has received the Honors of the Illinois Academy of Audiology and was named the Inventor of the Year for the Illinois University System. She has served on the American Academy of Audiology Board of Directors and has received the AAA Presidential Citation.

One award not listed above dates back to 1969 when Dr. Campbell was crowned her hometown Betty Crocker Homemaker of the Year. In the decades that have followed, she clearly has blended this childhood skill with her ever-increasing scientific knowledge, which no doubt led to her award-winning recipe “Pharmacologic Otoprotection Smoothie,” which can be found in the infamous cookbook How To Eat Like an Audiologist.

Fifteen years ago or so, Kathy wrote a 20 Questions article for me, and after all the scientific stuff was finished, we thought we’d add a Bonus Question. It went like this: Is it true that audiologists who study basic science aren't any fun at all? Her response: Nonsense. For example, we like to tell about the two molecules walking down the street. One molecule says to the other, “I just lost an electron” The other asks, “Are you sure?” and the first replies, “I'm positive!”

I’m also positive that you’ll enjoy the information that Kathy provides in her excellent 20Q article.

Gus Mueller, PhD
Contributing Editor

Browse the complete collection of 20Q with Gus Mueller CEU articles at www.audiologyonline.com/20Q

20Q: Ototoxicity and Audiology - Insights from an Innovator

Learning Outcomes 

After reading this article, professionals will be able to:

• Explain areas of study, training and recommendations for audiologists wishing to specialize in ototoxicity.
• Discuss aspects of clinical trials and testing of new technologies and pharmaceuticals including intellectual property protection and patents.
• List key highlights and challenges of research underway in regard to otoprotective agents and noise-induced hearing loss.

   Kathleen Campbell

1. You must be one of the first audiologists to work in ototoxicity and otoprotective agents. What drew you into this area?

I worked as a full-time clinician for 12 years before I received my PhD. During that time, I always liked the “puzzle cases” and ototoxicity definitely fit that category. At that time, we knew much less about the relative ototoxicity of various drug treatments and the overall effects on the auditory system. In addition, we knew little about the mechanisms of ototoxicity. So ototoxicity was an area rich for exploration.

Another major factor was that I found the ototoxicity cases to frequently have a great emotional impact on the patient, and sometimes on me. To see a child that previously had perfectly normal hearing and speech development but then had been suddenly deafened by an aminoglycoside was devastating to the child and family. I was in charge of auditory electrophysiology at the University of Iowa at the time, so the ABR that I ran was frequently the first confirmation of the loss.

The cisplatin patients were equally challenging. The ones I saw were often being treated with high dose cisplatin for ovarian cancer. That treatment protocol provided multiple challenges for them. Just think about it. The patient is now facing an illness that was almost always diagnosed at stage 4 and eventually terminal, the patient is immunosuppressed.  This means that they can’t be around children or grandchildren, with their frequent colds, and because friends and relatives frequently live at a distance, can only talk to them by phone (no text or email back then). So now they lose their high frequency hearing so they can’t hear children on the phone, and frequently, not even adults. And every month it is worse and just keeps progressing. Hearing aids were a problem because the hearing loss kept changing (no programmables at this time) and cisplatin patients frequently didn’t do as well with hearing aids as other patients with similar loss from other causes. So just when the patient is facing a life-threatening illness, they are losing their ability to connect with family and friends and put their affairs in order. The emotional impact on them was moving. They also often lost their ability to understand TV or enjoy music so their options for diversion, when they were too sick to go out and often too sick to read, became increasingly limited.

I was very frustrated at not being able to give them the help they really needed, but could just monitor their hearing loss as it progressed and try to advise them on ALDs and communication strategies. It wasn’t enough.

2. How did these experiences shape your career?

I found it intriguing that we might actually be able to prevent or treat some forms of sensorineural hearing loss. When I moved to Southern Illinois University School of Medicine to start the Audiology Program there, one of their basic science research strengths was pharmacology of the auditory system. But I needed more background in chemistry and pharmacology. So I wrote an NIH K08 Award grant to study ototoxicity in animals and humans, and to also take another 5 years of classes in chemistry and pharmacology. I will be ever grateful to them for that funding.

3. Is that the direction you would advise for other audiologists interested in this area?

Some of the best career advice for anyone is to find someone doing what you would like to do and then ask them how to get there. Not only will they be flattered but they will generally bend over backwards to help you make connections, share research, and often mentor you over the years. The good thing is that ototoxicity and otoprotective agent research has exploded over the last years so now there are many more universities and labs working in the area and now many opportunities are around. Another bonus for audiologists is that more and more agents are in or approaching clinical trials. That simply wasn’t the case 30 years ago. Now, a clinical audiology background is much needed and valued in taking the drugs through the pre-clinical and clinical trials process.

To really be able to understand and be a full part of a bench-to-bedside research team, the audiologist will need both a strong basic science and clinical background. A clinical audiology background combined with a PhD from an audiology program actively researching otoprotective agents is excellent, but also a clinical audiology background combined with a PhD in pharmacology or another related degree is also helpful.

The audiologist also needs to be very familiar with the ASHA and AAA guidelines for ototoxicity monitoring for clinical practice and for clinical trials. But for clinical trials, the audiologist will also need to be very familiar with CTCAE (Common Terminology Criteria for Adverse Events). CTCAE criteria are a standard classification system for the adverse of drugs used in cancer therapy but they are widely used in clinical trials for a variety of diseases and disorders.

Another way for audiologists to get involved is to serve on the committees writing guidelines. I worked on committees to help develop or revise the ASHA, AAA, and CTCAE guidelines. It was an excellent experience.

4. What other training would you recommend?

Certainly, the audiologist interested in this area should take some formal training in clinical trials including obtaining CITI certifications. Understanding patents and intellectual property issues will be critical if they are possibly working to develop their own agents or in working with other inventors or companies developing intellectual property. Many work environments including private industry, universities and NIH want their employees and grant recipients to understand intellectual property issues because without intellectual property protection many new ideas will never reach a patient. 

5. How do patents or other forms of intellectual property protection help get new technologies to patients?

In the public at large, there’s a lot of misunderstanding about intellectual property protection. Many people, including some scientists, believe it just restricts access and drives up the cost to the patient. Certainly, instances have occurred where companies try to extend patents to increase income and inhibit generics. But it is very unfortunate when an investigator immediately puts their new therapy idea in the public domain through presentation or publication without patent or other intellectual property protection. It isn’t just that they will make their employer unhappy or lose potential personal income. For example, if someone discovers a new drug that could reverse noise-induced hearing loss, publishes the idea and data without patent protection, they may never be able to patent it because they have placed in in the public domain. But to get that drug through the FDA approval process, including extensive pre-clinical and clinical trials testing, will cost hundreds of millions of dollars, if not well in excess of a billion dollars. Money in those amounts will have to come through a company which will eventually have to make a profit or at least break even. But without patents, the minute that drug is FDA approved, a different company, or multiple companies could immediately issue an immediate generic. Then, because the company producing generics did not have to spend millions in the development process they can sell the generic drug below the cost of the company that developed it. Consequently, without patent protection, no company can justify the cost of developing that new drug for patients and it may never be approved for human use.

6.  Interesting—I’ve never considered those aspects of the process. Have you been involved with all this?

Yes, I have helped several companies regarding testing various new therapies, by setting up their clinical trials to determine if their new drug has ototoxicity as a side effect. I have found that work to be some of the most rewarding and interesting that I do. I encourage other audiologists to get involved in that process so we accurately determine the ototoxicity of new drugs being developed. First, you really have to understand how the new drug they are testing works, and then determine how it might affect the auditory system.

 Here are just a few things that might need to be considered:

• Does it cross the blood-brain barrier and if so, could it affect the central auditory system?
• Can the drug reach the cochlea and if it does will it be toxic to the cochlea?
• Does the cochlea have receptors for the drug?
• Do you know how long it might be retained in the cochlea?
• Could it affect the vestibular system?
• If the drug affects bone growth, could it affect the ossicles or the internal auditory meatus

After you have determined all of what is known and what is not known, then you have to determine which tests will be needed in the clinical trials to assess those possibly affected areas in addition to more routine tests for hearing threshold, speech recognition, etc. You also need to determine how fragile the patients are to determine how much testing time they can tolerate and what concomitant factors they are likely to have that could impact results. You may also need to work with the company on determining any additional pre-clinical work that needs to be done. It is usually critical to work with the audiology clinical sites, particularly if they do not have an extensive history of collecting clinical trials data.

7. For clinical audiologists first working in clinical trials, what is their biggest challenge?​

Most audiologists are not used to the standardization and precision needed in clinical trial data collection. In clinical practice we focus on treating each patient individually and tailoring our approach to each case. We may use different tests on different patients. We may modify or abbreviate test procedures for an individual patient. One clinic may use different test materials than another clinic. We may reschedule a patient to a different day for the convenience of the patient or the clinic.

In clinical trials, the schedule and the test procedures are tightly controlled. It is the audiology consultant’s job to ensure that the testing conducted in France is the same as in Italy or the United States. You want to control every variable possible to ensure that the effect of the study drug is not lost in other variables. If testing involves different languages in different countries, you have to ensure that the translations are accurate and validated to a specific word recognition measure.  Self-assessment scales, such as Tinnitus Handicap Inventories and Dizziness Handicap Inventories, need to be scored exactly the same at every site.

Sometimes audiologists want to add additional tests for their own site or want to be able to use local standard procedures, but in a clinical trial, testing needs to be standardized across sites and any data collected has to be analyzed and shared so individual decisions don’t work. Naturally, if a patient has an adverse event, then follow-up is tailored to the needs of that particular patient.

8. What other problems related to clinical trials have you observed?

The clinical trial record keeping and the turnaround time for reporting can take some getting used to. Forms have to be filled out and filed with a very short turnaround. If an adverse event occurs that generally has to be reported within a day with immediate follow-up. Records have to be absolutely complete, retained and ready for review at any point in time.

9. Can any audiology clinic get involved in clinical trials?

It really depends on the clinical trial and the patient population. For rare diseases, you may need to collect data in multiple countries. One clinical trial I participated in involved over 100 countries. In those cases, you have to consider what testing you can do and still standardize and have trust in all of those sites. Not all countries use audiologists for testing and you have to consider the appropriate personnel qualifications in all of those sites.

Another simple consideration is that trial participants usually need to be tested on a rigid test schedule which cannot be varied if an audiologist gets sick or goes on vacation. Therefore, when first vetting the site you need to look at plans for backup coverage.

10. Are you amazed that anyone wants to sign up to be a test site?

Not at all! It is truly rewarding to be working on the cutting edge of a new drug being developed to help patients that currently have no good treatment options.

11. What is the current status of developing pharmacologic otoprotective agents?

That area continues to expand constantly! So many new agents and combinations of agents are being discovered in the lab that it can be hard to keep up with them all. But with that number of agents being developed, I have no doubt one will get over the finish line and I hope it is in the next few years. Some examples of areas where significant progress has been made over the past 10 or so years include:

1. Patient populations and protocols have been established for the conduct of clinical trials for testing otoprotective agents for cisplatin-induced hearing loss.
2. Patient populations and protocols have been established for the conduct of clinical trials to test otoprotective agents for noise-induced hearing loss testing for either temporary or permanent threshold shift.
3. Some clinical trials are going forward to test against aminoglycoside-induced ototoxicity in patients with cystic fibrosis.
4. Progress is also being made in exploring the efficacy of different drug delivery approaches; eg oral, iv, transympanic, or inhalation.

12. Has COVID been a problem?

COVID is a problem for everything. COVID impacts research labs by restricting personnel at universities. Some universities have had to pause their research entirely. Others have restricted the number of staff and students that can be on site at any time. Social distancing for lab work can mean that students are excluded or staff cannot work together. Shipping is often delayed. Trying to work from home as is often required, may mean you don’t have full access to lab equipment to run experiments.

13. How about COVID and clinical trials?

As you can imagine, many clinical trials simply had to go on hold. Patients and investigators simply cannot be placed at risk. Additionally, the drop in the economy affects the availability of investment funding for biotech companies to conduct drug development. Medical personnel have had to focus on COVID and for safety reasons, many areas needed for clinical trials are closed or restricted. I hope a vaccine will get us back to normal, but it won’t happen quickly.

14. Which area of ototoxicity research do you think will move ahead the fastest?

Several different agents are being tested for cisplatin-induced hearing loss and hopefully one of them will get over the finish line for approval in the next few years. Those clinical trials can proceed more quickly than in some other areas because the hearing loss usually develops within months rather than years so results can be seen sooner. Several otoprotective agents, meaning drugs that can prevent or treat hearing loss, are in development for cisplatin-induced hearing loss because cisplatin is still widely used although it is the most ototoxic agent in common clinical use. It is, however, very effective against many solid tumor cancers. Drugs in or approaching clinical trials for cisplatin-induced hearing loss are generally antioxidants and include D-methionine (D-met), ebselen, ACE-Mg, and N-acetylcysteine (NAC). Sodium thiosulfate has also shown some promise in reducing hearing loss in clinical trials but increased mortality and reduced disease-free survival in children with metastatic disease, which is very worrisome.

15. What are other areas of current research in this area?

Another area is aminoglycoside-induced ototoxicity. Several things have been happening on that front. First, some very effective antibiotics of various classes have been developed with little or no ototoxicity which gives physicians more options in addition to aminoglycosides. Plus, new aminoglycoside antibiotics with little or no ototoxicity are being developed. In fact, one was just approved last year. I was fortunate in being able to help with the clinical trials for some of those and it was very satisfying to see them get approved for patients. This means that is some cases, otoprotective agents may no longer be needed.

16. Will otoprotective agents for aminoglycosides be needed at all?

They are still needed. For example, individuals with cystic fibrosis often receive so many courses aminoglycosides over their lifetime that they are vulnerable to aminoglycoside-induced cochleotoxicity and vestibulotoxicity and some progress towards clinical trials has been made. However, the biggest need for otoprotective agents for aminoglycosides is in developing countries. For example, in some countries in South America and Africa, patients with multidrug-resistant tuberculosis (MDR-TB) are treated with high dose kanamycin for months on end. A high percentage of these patients end up with permanent moderate to severe sensorineural hearing loss. In my lab, I found that D-methionine could reduce kanamycin induced ABR threshold shift and outer hair cell loss in guinea pigs to near-normal levels. It was some of the strongest protection we’ve seen. I tried my best to get that to clinical trials but the logistics of clinical trials in some of the locations and patient populations in combination with the lack of any financial incentive for biotech in these largely impoverished countries precluded us from being able to go forward. The research is published so I hope it may move forward at some point (Campbell et al., 2016). At least we know how to do it in animals, and with a drug that has been tested in humans for other purposes.

ACE-Mg and ebselen have also shown some pre-clinical promise for reducing aminoglycoside-induced ototoxicity. NAC has shown variable results, exacerbating aminoglycoside-induced hearing loss in some studies and reducing it in others.

17. What about noise-induced hearing loss?

We’ve made a lot of progress in that area. Several agents have worked in the lab and some have made it to clinical trials. Noise-induced hearing loss poses many challenges in clinical trials. It is very difficult to identify clinical trials populations with sufficient numbers that unavoidably get noise-induced hearing loss in a short enough period of time to conduct a clinical trial, in a controlled environment. In some of the clinical trials, the incidence and degree of sensorineural hearing loss in the placebo groups was less than anticipated when the clinical trial was designed. It makes sense that when subjects know their hearing is being very carefully monitored that they are more proactive about using their hearing protection and reducing outside noise exposure. While we always want people to do everything possible to reduce noise exposures and use hearing protectors, that can render it difficult to see differences between placebo and study drug groups. 

18. What other new areas seem promising?

I find it very interesting that some researchers are looking at using otoprotective agents to reduce and control the damage from cochlear implant electrode insertion. That is an exciting area, particularly to help those individuals with remaining viable hair cell populations.

19. If you were considering doing an audiology-related PhD now but didn’t want to study otoprotective agents, which area would you choose?

I would study hair cell regeneration. That work is very exciting. Otoprotection is great for trying to prevent hearing loss or reversing it shortly after insult. But the idea that we could truly restore hearing to individuals with long-standing sensorineural hearing loss is just remarkable. That would be so very rewarding.

20. Any last words of advice for audiologists?

I have loved my career in audiology. It presents such a wide array of opportunities for helping people through clinical care, teaching, administration or research. There is never a reason to be bored in this field. So never be afraid to change things up in the course of your career and you are never too old to do it. I am so glad that I had many years of clinical work seeing a wide variety of patients. That experience served as the basis for everything else I did in teaching and research. Whether you are an AuD or PhD I would recommend never being afraid to take new courses in a new area and getting involved in teaching and research. I didn’t finish my PhD until I was 37 and then took another 5 years of coursework while working to develop a new area. No regrets at all. Never be afraid to keep learning and try something new. You never know what you can contribute until you explore it!

Further Reading 

If you’re interested in the topics that I’ve discussed here, here are some general references that you might want to check out.

Brock, P.R., Knight, K.R., Freyer, D.R., Campbell, K.C., Steyger, P.S., Blakley, B.W., Rassekh, S.R., Chang, K.W., Fligor, B.J., Rajput, K., Sullivan, M., & Neuwelt, E.A. (2012). Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 30(19), 2408–2417. https://doi.org/10.1200/JCO.2011.39.1110

Campbell, K., Claussen, A., Meech, R., Verhulst, S., Fox, D., & Hughes, L. (2011). D-Methionine (D-met) significantly rescues noise-induced hearing loss: Timing studies. Hearing Research, 282(1-2), 138-144.

Campbell, K., Hammill, T., Hoffer, M., Kil, J., & Le Prell, C. (2016). Guidelines for auditory threshold measurement for significant threshold shift. Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 37(8), e263–e270. https://doi.org/10.1097/MAO.0000000000001135

Campbell, K.C.M., & Le Prell, C.G. (2018). Drug-induced ototoxicity: Diagnosis and monitoring. Drug Safety, 41(5), 451–464. https://doi.org/10.1007/s40264-017-0629-8

Campbell, K., & LePrell, C. (2012). Potential therapeutic agents. Seminars in Hearing, 33(1).

Campbell, K.C., Martin, S.M., Meech, R.P., Hargrove, T.L., Verhulst, S.J., & Fox, D.J. (2016). D-methionine (D-met) significantly reduces kanamycin-induced ototoxicity in pigmented guinea pigs. International Journal of Audiology, 55(5), 273–278. https://doi.org/10.3109/14992027.2016.1143980

Claussen, A.D., Fox, D.J., Yu, X.C., Meech, R., Verhulst, S., Hargrove, T.L., Campbell, K.C.M. (2013). D-methionine pre-loading reduces both noise-induced permanent threshold shift and outer hair cell loss in the chinchilla. International Journal of Audiology, 52(12), 801-7. 

Fox, D.J., Cooper, M.D., Speil, C.A., Roberts, M.H., Yanik, S.C., Meech, R.P., Hargrove, T.L., Verhulst, S.J., Rybak, L.P., & Campbell, K.C. (2016). d-Methionine reduces tobramycin-induced ototoxicity without antimicrobial interference in animal models. Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society, 15(4), 518–530. https://doi.org/10.1016/j.jcf.2015.06.005

Gopal, K.V., Wu, C., Shreshta, B., Campbell, K.C.M., Moore, E.J., Gross, G.W. (2012). d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks. Neurotoxicology and Teratology, 34(5), 495-504. doi: 10.1016/j.ntt.2012.06.002

Hammill, T.L., & Campbell, K.C. (2018). Protection for medication-induced hearing loss: the state of the science. International Journal of Audiology, 57(sup4), S67–S75. https://doi.org/10.1080/14992027.2018.1455114

Le Prell, C.G., Johnson, A.-C., Lindblad, A.-C., Ulfendahl, M., Campbell, K.C.M., Kujawa, S.G., Green, G.E., Miller, J.M., & Guire, K. (2011). Increased vitamin plasma levels in Swedish military personnel treated with nutrients prior to automatic weapon training. Noise Health, 13(55), 432-43.

Tieu, C., & Campbell, K.C.M. (2012). Current pharmacologic otoprotective agents in or approaching clinical trials: How they elucidate mechanisms of noise-induced hearing loss. Journal of Otolaryngology, 3, 130. https://dx.doi.org/10.4172/2161-119X.1000125