Editor's note: This popular story from the Daily Briefing's archives was republished on June 9, 2020.

For 26 years, Jasmin Barman-Aksözen suffered inexplicable severe pain when exposed to sunlight—until her own research led to a diagnosis for a rare disease called erythropoietic protoporphyria. In an editorial in Medicine Access @ Point of Care, Barman-Aksözen details how she helped develop the cure to her disease and her battle to get it approved.

Start creating and promoting your patient education tools

How she learned of her disease

Throughout her childhood, Barman-Aksözen would suffer "unbearable burning pain" after spending even a short time outdoors, she writes. The pain would leave her "in agony for days." During that time, she recalls, "I was unable to go to school, to sleep, to tolerate even weak light exposure, or the body heat of my parents as they tried to comfort me."

No treatment worked, Barman-Aksözen writes. Even worse, classmates, teachers, and physicians didn't believe Barman-Aksözen when she told them about her symptoms.

Then in 2006, 26 years after her symptoms began, Barman-Aksözen discovered an article online about EPP, "a lifelong, inherited condition associated with a higher rate of fatal liver failure," she writes.

At the time, Barman-Aksözen was a student of molecular biology and began researching EPP. At last, She Barman-Aksözen writes, it became clear why sunscreens never helped": the condition causes a buildup of the chemical protoporphyrin in the skin, which makes the skin very sensitive to light and "triggers the so-called 'phototoxic reactions,' burn-like injuries of the blood vessels and the surrounding tissue."

Armed with information, Barman-Aksözen insisted a dermatologist test for the condition,  Barman-Aksözen recalls. The test confirmed her diagnosis, but "no therapy yet existed to prevent the painful phototoxic reactions," she writes.

Barman-Aksözen's interest in EPP eventually led her to accept a PhD position with Elisabeth Minder, head of the Swiss Porphyria Reference Centre (SPRC) whose team had been testing EPP treatments. Today, Barman-Aksözen is the head of the clinical chemistry laboratory at the SPRC.

The development of EPP's cure

Shortly before Barman-Aksözen joined the SPRC, Minder had begun a small clinical trial testing the use of an active compound called afamelanotide on five EPP patients. The idea came from Rocco Falchetto, a biochemist and EPP patient, who thought enhanced pigmentation of the skin could filter visible light from penetrating the skin, and thus prevent the painful phototoxic reactions. Afamelanotide induces melanin production in the skin and activates a strong anti-inflammatory and anti-oxidative cellular defense system, Barman-Aksözen explains.

The results of a larger international trial, published in the New England Journal of Medicine, showed participants were able to spend significantly more time outdoors and expose themselves to an additional 28.6 hours of direct sunlight without developing any reactions, compared with the control group, Barman-Aksözen writes.

In 2008, afamelanotide was given orphan drug status by the European Medicines Agency (EMA), and after use by 115 Italian and Swiss patients, physicians discovered the drug was safe long-term and saw a treatment adherence rate of over 94%, Barman-Aksözen writes.

Barman-Aksözen, too, has used the treatment since 2012 and seen significant results, she writes.  

The battle for approval

In 2012, EMA began the official approval process for afamelanotide, and given the existing evidence, Barman-Aksözen writes that she and her colleagues anticipated the approval would move quickly.

However, the rapporteurs—the people appointed to report on the meeting proceedings—for the EMA questioned afamelanotide's benefits and whether the treatment would be beneficial to patients. According to Barman-Aksözen, the EMA rapporteurs had applied a different calculation, called Hodges–Lehmann shift estimator, to the clinical trials data and divided the remaining time in the sun by the clinical trials entire 180-day period. As such, they concluded there was "a benefit of 8 min per day only."

Barman-Aksözen takes aim at these changes. She argues that the Hodges–Lehmann shift estimator is an "unusual way to calculate the median" and the reliance on "an average outcome to calculate effectiveness makes little sense," as it fails to take into account that the trial period included rainy days with no sunlight and that the trial participants were limited in their exposure outdoors by working hours.

After allowing testimony from patients and caregivers, EMA in October 2014 "recommended afamelanotide for approval under exceptional circumstances for the prevention of phototoxicity in adult patients with EPP," Barman-Aksözen writes.

But nearly five years later, Barman-Aksözen writes, "most EPP patients in Europe … still do not have access to the" treatment as they must first be approved each countries' national health systems, Barman-Aksözen writes.

In Germany, the G-BA, its national competent authority questioned the benefits of afamelanotide based on the EMA calculations, Barman-Aksözen writes.

However, after a written statement from Barman-Aksözen and Minder, the G-BA changed its assessment and agreed the benefit was "not quantifiable," essentially approving the treatment under EMA's exceptional circumstances rules. As a result, since April 2017, all EPP patients in Germany have had access to afamelanotide, Barman-Aksözen writes.

In England, the National Institute for Health and Care Excellence (NICE) reviewed EMA's document on afamelanotide and, even after hearing from experts and patients, the committee decided there was not enough benefit to recommend the National Health Service cover the treatment.

Stakeholders appealed the ruling, and an appeal panel concluded that NICE had acted unfairly and expressed concern over "whether the methodology used in the evaluation discriminates against patients with EPP," Barman-Aksözen writes. NICE then held a new committee meeting in March 2019, and as of Barman-Aksözen's writing, NICE had yet to make its decision.

As for the United States, FDA granted afamelanotide orphan drug status in 2008, but has not yet approved the drug, Barman-Aksözen writes.

A call for more patient voices

Barman-Aksözen writes that the story highlights the need for "highly empowered patient" to be involved in approval discussions for treatments. She concludes, "[I]t is urgently necessary to improve appropriate inclusion of the patient perspective in order to ensure that decisions reflect outcomes that are relevant to the patients" (Barman-Aksözen, Medicine Access @ Point of Care, 8/6; Weintraub, STAT News, 1/2).