As an ophthalmologist, I had attended AAO meetings on many occasions, but there I was in November 1995 attending as an exhibitor for the first time. I had launched TheraTears about 4 months earlier. My company, Advanced Vision Research (Woburn, MA), was so new that it was not on the Academy's mailing list, and because I had no idea when to sign up for space, I signed up late. As a result, we were in the back of the hall, with a borrowed display, in a booth next to a Brazilian company that was selling used ophthalmic equipment. At that time, TheraTears was available in only a handful of stores—we were selling it primarily by mail order to patients. Yet, as the doors of the exhibit hall opened on that morning in November, I was determined to convince every ophthalmologist there to prescribe TheraTears to their patients. After 18 years of research, I truly believed TheraTears was the only eye drop for dry eye that actually worked, and that it was destined to become the best-selling treatment for dry eye in the world. Not if, but when.

THE BEGINNING
It all started as a summer project when I was a medical student at Columbia's College of Physicians and Surgeons. The Dean's committee was giving out $1,000 stipends to students who wanted to conduct research during the summer. It was a competitive situation—there were about 20 stipends to be distributed based on a committee's evaluation of an applicant's research plan. My plan was to develop a method for measuring the osmolarity of tear microvolumes in patients with dry eye that could be used as a diagnostic test. Out of about 25 proposals submitted, mine was ranked at the very bottom. There would be no funds coming from the committee. I thought it still seemed like a good project, however, and when Linsy Farris, MD, offered me $1,000 out of his own pocket to make the left-for-dead nanoliter osmometer in his lab work, my plans for the summer were sealed.

So there I was, at the start of summer vacation in 1976, sitting in a small lab by myself in front of a Clifton Nanoliter Osmometer (Clifton Technical Physics, Hartford, NY). I read the manual, followed the instructions, loaded the test standards, and watched under the microscope as the sample platform frosted over, completely obliterating my view. I saw that I was not going to figure this machine out in one day. After several hours of making small modifications to the operating procedure, I decided to head for the library to read about dry eye. This became my daily routine—to tinker with the machine in the morning and read about dry eye, the tear film, and the cornea in the afternoon.

The thinking at the time was that dry eye was caused by dry spots. But the more I read, the less sense this made. It had been shown, for example, that approximately half of dry eye patients had a normal tear film break-up time. How can something cause a disease if half the patients don't have it? Another popular theory was that dry eye was the result of a direct attack on the eye's surface, independent of the decrease in tear production. But researchers had shown that patients who had their lacrimal glands surgically removed for epiphora developed the same ocular surface changes as patients with Sjögren's syndrome. On the other hand, Henrik Sjögren, MD, in his light microscopy studies, had described water moving across the conjunctival epithelium, as if pulled by some force. I looked at his pictures. Osmotic force, I thought. It was increased osmolarity that was causing the ocular surface disease in dry eye! I remember sitting there in the library with goose bumps on my neck as I realized the importance of this insight. I wrote my first National Eye Institute (NEI) project grant with a pad and pencil on my kitchen table. The NEI proceeded to fund my dry eye research, and I arrived in Boston in 1980 with a fully funded NEI project grant.

THE SECOND FLASHING LIGHT BULB
As I began experimenting with hypotonic tear solutions that were formulated at the hospital pharmacy to my specifications, it became statistically clear from my small studies that dry eye patients preferred hypotonic over isotonic solutions, but these results did not knock me over. I had the distinct feeling I was missing something, and then suddenly, I found “it.” I was reading an article about conjunctival permeability and the blood-tear barrier when the second light bulb started flashing. The blood-tear barrier—there were living cells on the eye's surface! What did living cells need from a blood supply? What did the living cells on the eye's surface need from the tear supply? Oxygen and electrolytes!

I designed and completed experiments, and produced a flood of statistically positive and dramatic results over several years. It was probably the most exciting time of my life—making an original, permanent, and lasting contribution that would help other people. The solution that I eventually called TheraTears was shown to restore conjunctival goblet cells, restore corneal glycogen levels, and reduce rose bengal staining. In addition, it promoted healing in both dry eye rabbit models and in dry eye patients.

I THOUGHT THE HARD PART WAS OVER
Any doctor or scientist looking at these results or trying the eye drop would be amazed at the potential, right? All I was asking for was $150,000 up front and a 5% royalty. I thought it would take about a week to license the TheraTears patent. Nobody returned my calls the first week. I eventually offered the technology to every significant pharmaceutical company I knew of. Twice. As unbelievable as it now seems, nobody wanted it. “The doctors will never believe you.” “We have our own research program.” “We don't know how we would market this.” “We have a full tear line already.” “The research is good, but the problem is that you have done all of it yourself.” “It's good, but do you mind if we add benzalkonium chloride?” It was becoming increasingly clear that, if I wanted to bring TheraTears to market, I would have to do it myself. That's one person and about $30,000. No problem.

Along the way, I had taken a 1-hour adult education course on how to run a mail-order business. I learned to start small with a one-page catalogue, and to accept orders with credit card numbers before the product hits the warehouse so that you have cash before the bills are due. As word got out about what I was developing, patients began contacting me about TheraTears. Over a period of approximately 10 years, I placed these patients' names and addresses on a “Rapid Notification List” that I would use to contact them when the product was available. I found a manufacturer who begrudgingly agreed to do what is known as “scale up and manufacture” for TheraTears (convincing them was more difficult than getting into medical school). For “marketing,” I picked up a marketing book by Jay Conrad Levenson in the dollar book bin at Staples. It was excellent; I read it twice. All this preparation came together in a direct-mail piece that I sent out to The Rapid Notification List. The mailing consisted of a cover letter on my practice letterhead (there was no company letterhead), and a one-page order form with pricing and ordering information, including a request for the name and address of the patient's doctor. My cover letter was signed in ink, and there were real postage stamps on the envelopes. Some patients had moved without a forwarding address, but most letters were received and TheraTears orders came in. And once the orders came in, TheraTears orders went out along with personalized letters to the patients' doctors. I asked patients to see their eye doctors about 4 to 6 weeks after starting TheraTears, and they did.

Now, what would you find more convincing? A guy in a suit with a four-color brochure, a pretty picture of a lubricant eye drop and a case of samples, or that dry eye patient you have been trying to treat for the past 5 years who comes into your office telling you he has finally found an eye drop that really works? No contest. As they say, the rest is history.

SUCCESS
The first patient I treated with commercially available TheraTears came to my office in 1995 with mild dry eye. I prescribed TheraTears for her and instructed her to return in 4 weeks. When the patient returned 4 weeks later, I asked her whether she was still using TheraTears four times a day. “No,” she replied. I turned white, took a deep breath, and asked her why. “Because my eyes don't bother me anymore,” she replied.

There are patients in my practice with severe dry eye from Sjögren's syndrome who have been using TheraTears now for years. Dry eye is no longer a significant problem in their lives. As an eye physician, there is nothing more gratifying than being able to help so many dry eye patients, both nationally and around the world.

FAST FORWARD
TheraTears is now available in more than 50,000 retail locations across America, including every major drug chain, superstore, and most food markets. We launched the bottled version of TheraTears, with a disappearing preservative, in March 2000. Two years later, we launched preservative-free TheraTears in Canada, and we have just received CE Mark approval for TheraTears marketing throughout the European Common Market. Current Nielsen IRI data show that TheraTears is the fourth best-selling lubricant eye drop brand in drugstores, and the fastest growing major lubricant eye drop brand in the US. This year we will be in the Inc 500, a list of the 500 fastest growing privately held companies in America. I owe thanks to my wife, who has supported me throughout this adventure, and who always greets me at home with a smile no matter what time it is. I also owe thanks to what has grown to a team of six dedicated, talented, and passionate employees who complement my own strengths and interests, and who keep me focused.

There is a very active new product pipeline at Advanced Vision Research. Each product we launch will be totally unique, a category creator, and will really work. For example, imagine a pill that improves dry eye without any side effects. Stay tuned for TheraTears Nutrition for Dry Eyes. . .

Innovators is a monthly column that offers insight into how physicians bring their ideas to market.
Jeffrey P. Gilbard, MD, is the founder, president, and CEO of Advanced Vision Research in Woburn, Massachusetts. He also serves as Clinical Assistant Professor of Ophthal-mology at Harvard Medical School, and Clinical Associate Scientist at the Schepens Eye Research Institute. He is in private practice with Tallman Eye Associates in North Andover, Massachusetts. Dr. Gilbard may be reached at (781) 932-8327; jgilbard@theratears.com.