Sildenafil: 25 Years Later – Summary
Twenty-five years ago, the FDA’s approval of sildenafil (Viagra) radically reshaped the treatment of erectile dysfunction. Editor-in-Chief of Grand Rounds in Urology, E. David Crawford, MD, sits down to discuss the history and future of PDE5 inhibitors with three of the people responsible for their initial approval: Mark Hirsch, MD, Raymond Rosen, Ph.D., and Irwin Goldstein, MD.Dr. Hirsch, Dr. Rosen, and Dr. Goldstein reflect on the approval process, particularly the development of the International Index of Erectile Function (IIEF) in response to the need for sensitive, reliable, and validated measures for Phase 3 outcomes. They give their perspectives on the benefits of PDE5 inhibitors have had on patient QoL over the past 25 years, and the treatment advantages it gives physicians today. They conclude by discussing ideas for the future of PDE5 inhibitors, including the potential benefits and obstacles for over-the-counter PDE5 inhibitors, and possible expansion of conditions treatable by sildenafil.
About the Panel
Irwin Goldstein, MD, is Director of Sexual Medicine at Alvarado Hospital, Clinical Professor of Surgery, and Voluntary Clinical Professor of Obstetrics, Gynecology & Reproductive Sciences at the University of California San Diego, and practices medicine at San Diego Sexual Medicine. He is also Editor-in-Chief of Sexual Medicine Reviews and past Editor of The Journal of Sexual Medicine. He is a Past President of the International Society for the Study of Women’s Sexual Health (ISSWSH) and of the Sexual Medicine Society of North America (SMSNA). He holds a degree in engineering from Brown University and received his medical degree from McGill University. The World Association for Sexual Health awarded the Gold Medal to Dr. Goldstein in 2009 in recognition of his lifelong contributions to the field, in 2012 he received the ISSWSH Award for Distinguished Service in Women’s Sexual Health, in 2013 he received the Lifetime Achievement Award from the SMSNA, and in 2014 he received the Lifetime Achievement Award from the International Society for Sexual Medicine. He is happily married to his college sweetheart Sue, and together they have three children and five grandchildren.Mark Hirsch, MD, has been involved in scientific and clinical research on erectile dysfunction (ED) for the past 32 years. Beginning with a 1990 fellowship in male sexual dysfunction (with Dr. Arnold Melman at the Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York) and continuing with a 25-year career (to date) as a medical officer and medical team leader at the Center for Drug Evaluation and Research (CDER) in the United States Food & Drug Administration (FDA), Dr. Hirsch has consistently advocated for the health and well-being of men with ED. Under the tutelage of Drs. George Christ and Arnold Melman, and Dr. Hirsch participated in both bench and clinical research related to ED. As CDER/FDA medical team leader in urology for the past 23 years, Dr. Hirsch has played an active and ongoing role in the development of safe and effective drugs for the treatment of various urological conditions, including drugs for the treatment of ED.
Raymond Rosen, PhD, founded and co-directed the first inter-disciplinary training program in Sexual Health with Dr. Sandra Leiblum, and served as founding director of the Comprehensive Sleep Disorders Center. Other academic and administrative positions during his 35-year tenure at Robert Wood Johnson Medical School include Chief Psychologist in the Department of Psychiatry and Director of Medical Education in Psychiatry from 1992-2001. He also served as Chair of the Medical School Appointments and Promotions Committee and Associate Dean of Robert Wood Johnson Medical School from 2001-2003. In 2007, he accepted a full-time appointment to New England Research Institutes (NERI) and served as Chief Scientist at NERI until 2018. He serves currently as a Full Adjunct Professor in the Department of Psychiatry at the University of California, San Francisco (UCSF) School of Medicine and as an adjunct professor of Medicine at Rutgers – Robert Wood Johnson Medical School.
Grand Rounds: 25 Years of PDE5 Inhibitors in Urology
Welcome to our latest Urology Round Table Discussion. This year marks the 25th anniversary of the FDA approval for the first PDE5 inhibitor used to treat erectile dysfunction (ED)—sildenafil, commonly known as Viagra, or the little blue pill.The History and Impact of PDE5 Inhibitors
Originally developed for cardiovascular disease, early research on PDE5 inhibitors unexpectedly revealed their high efficacy in treating ED, leading to the FDA’s approval. This milestone had a significant cultural and medical impact worldwide.As urologists, many of us see patients for various issues—kidney stones, urinary concerns—and just as they’re leaving, they ask, “Hey, Doc, can we talk about that pill for erections?” It’s clear that this drug transformed sexual health discussions and redefined treatment options.
Expert Panel: Pioneers in PDE5 Research
Joining me today are three key figures in the research, approval, and ongoing use of PDE5 inhibitors:- Dr. Mark Hirsch – A urologist who has served for years in the FDA’s Division of Urology, Obstetrics, and Gynecology, and is currently a medical team leader in urology at the FDA.
- Dr. Ray Rosen – A renowned researcher and Adjunct Professor of Psychiatry at UCSF School of Medicine, instrumental in the development of clinical trial outcome measures for PDE5 inhibitors.
- Dr. Irwin Goldstein – Director of Sexual Medicine at Alvarado Hospital, Director of San Diego Sexual Medicine, and Editor-in-Chief of Sexual Medicine Reviews. He was one of the earliest researchers studying the physiology of erectile function and the mechanism of PDE5 inhibitors.
The Early Days: Bringing PDE5 Inhibitors to Market
Dr. Mark Hirsch on the FDA’s Role in Approval
Q: Dr. Hirsch, take us back 25 years—what led to the investigation of PDE5 inhibitors for ED, and what role did the FDA play?Dr. Hirsch: There was a clear need for better ED treatments beyond penile injections, prostheses, or vacuum devices. The FDA recognized this and encouraged rigorous research. We worked closely with pharmaceutical companies, academic researchers, and social scientists to ensure the drug was safe and effective. I’m honored to have been a part of the process alongside pioneers like Dr. Goldstein and Dr. Rosen.
Dr. Ray Rosen on Developing ED Measurement Tools
Q: Dr. Rosen, what were the challenges in designing clinical trials for PDE5 inhibitors?Dr. Rosen: The biggest challenge was the lack of validated measurement tools for assessing erectile function. Early trials used rigid scanners to measure penile circumference, but this wasn’t practical for large-scale clinical trials.
To address this, we developed the International Index of Erectile Function (IIEF)—a patient-reported outcome measure that became the industry standard. I’m proud that we negotiated with Pfizer to ensure that the IIEF remained in the public domain from day one, allowing all researchers to use it freely.
Dr. Irwin Goldstein on the Science Behind PDE5 Inhibitors
Q: Dr. Goldstein, can you share insights into the science behind PDE5 inhibitors and their impact?Dr. Goldstein: My mentor, Dr. Bob Krane, and I spent 25 years studying erectile physiology. Until 1991, we didn’t even know the biochemical mechanism of erections! Our research revealed that nitric oxide (NO)—a gas—was the key neurotransmitter for penile erection.
Around the same time, Pfizer researchers noticed a surprising side effect in cardiovascular studies—improved nocturnal erections. This led to a shift in focus from treating angina to treating ED. I worked with Pfizer’s scientists to design Phase 2 and Phase 3 clinical trials, ensuring they had appropriate safety and efficacy endpoints.
When the landmark New England Journal of Medicine paper was published, I was the first author, and my phone didn’t stop ringing for weeks!
The Cultural and Medical Impact of Viagra
Dr. Rosen: The introduction of oral ED treatments democratized sexual medicine. ED management moved beyond urology specialists to primary care physicians, making treatment more accessible and reducing stigma.Dr. Goldstein: The approval of Viagra was a game-changing moment in medicine. It gave men a non-invasive, highly effective treatment, fundamentally improving quality of life.
Dr. Hirsch: The FDA’s rigorous review ensured that PDE5 inhibitors were safe and effective, setting a gold standard for future drugs.
The Future of PDE5 Inhibitors
1. Will PDE5 Inhibitors Become Over-the-Counter (OTC)?
Dr. Goldstein: The future is definitely OTC, likely with behind-the-counter restrictions to ensure safe use—especially for patients on nitrates. Making PDE5 inhibitors more accessible would reduce reliance on unsafe, unregulated supplements.Dr. Hirsch: The FDA’s approval process for OTC status is rigorous. Patients must be able to understand labels, self-select properly, and use the drug safely. We will assess the data just as rigorously as we did 25 years ago.
2. Expanding PDE5 Inhibitor Use Beyond ED
Dr. Rosen: PDE5 inhibitors are now being explored for pulmonary hypertension, Raynaud’s disease, and even reproductive health in women. There’s even discussion about their potential role in preventive cardiology—bringing us full circle to where the research originally began.Final Thoughts
Dr. Hirsch: It’s been an honor to be part of this historic journey and to work with brilliant researchers like Dr. Rosen and Dr. Goldstein. The FDA remains committed to ensuring safety and efficacy as we explore new applications.Dr. Rosen: PDE5 inhibitors have revolutionized sexual medicine, bringing ED treatment into mainstream healthcare.
Dr. Goldstein: This 25-year milestone is a celebration of innovation in sexual health. With ongoing research, the best is yet to come.
Host: Thank you to Dr. Hirsch, Dr. Rosen, and Dr. Goldstein for sharing your expertise. We look forward to reconvening in the future—maybe in another 25 years or sooner—to discuss new breakthroughs in urology and sexual medicine.
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