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Part Two: Darwin’s Orphan - A Childhood With Epidermolysis Bullosa

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Editor's Note

In this three-part Mighty feature, we explore what it really means to have an “orphan disease” — the name for conditions that affect less than 200,000 people in the U.S. There are 7,000 orphan diseases, collectively affecting 10 percent of the U.S. population. 

In this three-part Mighty feature, we explore what it really means to have an “orphan disease” — the name for conditions that affect less than 200,000 people in the U.S. There are 7,000 orphan diseases, collectively affecting 10 percent of the U.S. population. 

Part One follows John Hudson Dilgen, a teenager with epidermolysis bullosa (EB), an extraordinarily painful orphan disease. Part Two widens the lens to explore orphan diseases more broadly from the clinical and policy perspective. Part Three turns the camera around, to consider the similarities, today and tomorrow, between orphan and common diseases. It concludes: we are not so different.

Part Two: Them

For better or worse, this story is not just about John. This story is not just about Faye, nor the tribulations of the subclinical world. This story is not just about Dr. Tolar, nor the challenges of preclinical science. This story is not just about EB. It is a social story, of systems and values. It is the orphan story.

Of the many people with orphan diseases, more than two-thirds are children (23). Up to 90 percent of conditions are considered “serious or life-threatening” and one in three children die by their 5th birthday (24, 25).

On average, orphan diseases take seven years to diagnose, and one in 10 are misdiagnosed during this time (26, 27). For the fortunate patients who receive an accurate diagnosis, in 2013, only one in 20 had pharmacologic treatments. Few of those are curative (28, 29).

This begs the question: what is the role of medicine when it can’t cure? And, what are those who so longingly desire to propel it forward to do in the meantime?


On October 4, 2010, an Institute of Medicine (IOM) investigation committee chaired by Thomas Boat publicized these figures to the medical community. Dr. Boat had a personal stake: his granddaughter Katie had been diagnosed with a brain tumor called neuroblastoma (most childhood cancers are orphan diseases on a prevalence basis). Katie went through chemo. Her tumor killed her within two years of diagnosis. Katie died before her 4th birthday.

The experience prompted two revelations for Dr. Boat: firstly, “medicine rarely cures, even today.” Secondly, “care has context.” To this end, he noted that “improvement of welfare is a really important outcome… on par, or even above, prolonging life.”

A JAMA paper by Thomas Lee titled “Zero Pain is Not the Goal” asks a similar question. He wrote, “What should healthcare be trying to accomplish?”

Pain is part of life and part of medicine. Suffering is… inherent to medicine; the word “patient” comes from the Latin for “one who suffers.” Patients want efficient relief from their symptoms, of course, but… patients place greater emphasis on the how (whether they are receiving care that is compassionate, coordinated and focused) than the what (whether their pain is completely controlled). Zero pain is not always the goal. The reduction of suffering often is, and that is something more complex than analgesia alone.

Dr. Lee’s ethos is that patients crave good interactions over perfect lab values. For patients like John, aiming for perfect medicine can be the enemy of good care (31). Dr. Boat’s conclusion was similar: “We know what to do, but not how to do.” (1, 30)


While the orphan disease story exploded with the IOM report, the narrative commences in the early 1980s. On a quiet Wednesday evening during the ides of March, an episode of “Quincy,” a popular medical mystery series, aired on TV. The episode, titled, “Seldom Silent, Never Heard,” featured the titular coroner investigating the homicide of boy who had uncontrolled Tourette’s syndrome (32).

The backdrop of the episode was a 1980 appeal of a Tourette’s patient to the House Subcommittee on Health and Environment for development of therapies for rare diseases. The star of “Quincy,” Jack Klugman, caught wind of the hearing — his brother had a rare cancer — and took to convey the message through his medium (33).

The screening impelled a sequence of events that led to a testimony by Klugman to Congress in 1981, the introduction of a bill by Representative Henry Waxman in 1982, and its passage in 1983 (34). Deemed the Orphan Drug Act (ODA), it drew its name from a statement by Waxman that patients with rare diseases, in lieu of therapeutic options, “are very much like children without parents.” (35) The ODA was primarily concerned with the provision of incentives to pharmaceutical companies to facilitate investment in drug development for orphan diseases (36).

Marlene Haffner, the first director of the FDA’s newly minted Office of Orphan Products Development (OOPD), is petite in stature, with closely cropped graying hair and a slow, deliberate drawl. She fell into this line of work “rather randomly.” As Dr. Haffner recalled, her early career was shaped by time working for the Navajo in New Mexico: “There I was on the reservation, seeing a group of underserved, dealing with… methemoglobinemia, tularemia, plague…[illnesses] that almost didn’t exist anymore in Western society.” The parallels between diseases forgotten on differential diagnoses and those erased from them are manifold.

By the time Dr. Haffner was running the OOPD, she had learned a key lesson in “how”: that “ivory tower medicine is ineffective” in certain habitats. Her doctrine is steeped in practical considerations of culture, of terroir. These talents translate profoundly for “parents with a new diagnosis that often they can’t even pronounce.”


From the outset, Representative Waxman, and a mother from Connecticut named Abbey Meyers, understood the importance of the language barrier faced by families airdropped into hostile illness terrain. Ms. Meyers, an activist whose son had Tourette’s, was a driving force behind the ODA legislation. Her own dispatch occurred watching her as-of-yet undiagnosed son David flail uncontrollably while attempting to read a comic strip. To avoid tears, she reached for a Parade magazine. The cover story was on a child with Tourette’s. She called to her husband with a simple refrain: “Come here, I found out what’s wrong.” He responded in disbelief: “Whoever heard of a diagnosis made by a Sunday magazine?” With a new Monday on the horizon, the Meyers’ only question was, “Where do [we] start?”(37)

They started by founding the National Organization for Rare Disorders (NORD). This “coalition” was an effort to ally families with rare diseases under one banner, for purposes of support, education, fundraising, advocacy, and lobbying (38). It was a motley nation, consisting of parents from dispersed pathological city-states, a federation united in the face of overwhelming odds. The founding history is intensely American. Appropriately, NORD was inaugurated at a backyard barbeque.

Meyers wrote, “Hope is like a road in the country; there never was a road, but when many people walk on it the road comes into existence.” (37) In the time since NORD trod the path less traveled, it has paved the highway for those in its wake: today, NORD serves 260 patient organizations and contains information on more than 1,200 diseases (39).

That singular, slippery question — Where do we start? — is a common one encountered by families like the Dilgens. NORD serves 7 million users, and on Orphanet, the European analog, half of the visitors are first-time users (40). With regards to “diagnosis through the Sunday magazine,” 93 percent of these users are either seeking specific disease information or a support group, and the majority of patients find Orphanet through Googling (41). Most patients with orphan diseases see at least three doctors before the correct diagnosis is made (42). The so-called diagnostic odyssey, an incessant brand of limbo, persists.

Furthermore, in an age of alternative facts, information veracity is critical: while 87 percent of patients ascribe at least some importance to internet-sourced information, only one in 25 sources is certified by verification agencies (43, 44). The shelters built by communities like NORD simultaneously provide a refuge amidst the burdens of reality and a refuge from the dangers of fallacy.

But these tribes are important beyond rote information. Acceptance into a tribe engenders a sense of identity. Andrew Solomon characterized the relationship of illness and identity to astonishing effect in his landmark work, “Far From the Tree“:

We often use illness to disparage a way of being, and identity to validate that same way of being. This is a false dichotomy…Many conditions are both illness and identity, but we can see one only when we obscure the other. Identity politics refutes the idea of illness, while medicine shortchanges identity. Both are diminished by this narrowness. (45)

A diagnosis medicalizes a set of symptoms; appearance devolves into illness; irregularity degenerates into pathology. Such medicalization is accompanied by a prognosis, almost always poor, and certainly never “normal.”

Yet illness, to the extent it fosters community and vanquishes isolation, can be enlivening. Per Solomon: “Acceptance allows children to become most fully themselves… fully recognized citizens of the tiny nation that is family.”(45)


Still, disease communities may offer more than knowledge and empathy. Their worth is not restricted to the past and present. They can be productive. They can impact the future.

Pat Furlong — a former nurse, mother of two boys with Duchenne’s Muscular Dystrophy (DMD), and founding CEO of Project Parent Muscular Dystrophy (PPMD) — has embraced this mantra. She is a Valkyrie, a tireless admiral against the unrelenting tides of disease and an inexhaustible general against the inhospitable landscape of bureaucracy. This is despite the death of both of her children 8,400 days ago.

To Furlong, a diagnosis is but lexicon, a “verbal confirmation of what you already knew.” Thus, “you need to separate the diagnosis [and prognosis] from the little boy who’s still the little boy… not talk about what will happen later.” Instead, Furlong prefers to discuss what might happen later. “There’s always something to do,” she avows. Her crowning achievement: 21 years after her children died, the FDA approved the first drug indicated for DMD (46).

Organizations like Research!America, the largest and oldest “nonprofit advocacy alliance,” provide the megaphone for lobbying in Washington. It was founded by, among others, Mary Lasker — the marketing savant turned activist who almost single-handedly convinced Nixon to declare the “War on Cancer.”

Mary Woolley, current CEO and Lasker incarnate for orphan disease, believes within the “flawed system in D.C.” (which is neither “neat nor linear”) all of the “biggest steps forward have come from the patient community.” They have not, she emphasizes, come unilaterally from “the findings of science.” The key to policy change is about “meeting at the heart before getting to the mind.” Facts are informative but not necessarily influential. Per Woolley, lawmaker decisions are “more often emotional than evidentiary.”

Thus, Research!America is a Rosetta Stone between scientific semantic and lawmaker lingo. For Woolley, since it is “underrealized that all of science’s activities take place within a public context,” the optimal path forward entails “standing shoulder to shoulder with patient families.” This narrative reverberates through the hallowed historical halls: the March of Dimes, the War on Cancer, and the AIDS Movement followed an analogous route.

Furlong echoes the sentiment. Reflecting on the past, she recounted, “Thirty years ago, there was no village — only two boys in Middleton, Ohio, with DMD.” Observing the present, she remarked PPMD, a “grassroots” movement, had provided a “compass,” a vector, with which to “raise our voices and accelerate research.” Envisioning the future, she hopes “we can keep our sons on their feet.”

In DMD, a child’s ability to stand is more than metaphor. It is a proxy for mortality.


“Godforsaken Collagen VII,” Alex Silver retorts when you dare mention the protein-that-shall-not-be-named. Silver, founder of the EB Research Partnership (EBRP), is a financier by day and a crusader by night. He emanates the zeal, devotion, and grit to match. He holds a gripping gaze and opines with fervor, frequently forced to brush his salt-and-pepper hair out of his eyes.

Silver’s son, Jackson Gabriel Silver, has EB. The story of Jackson’s diagnosis is eerily similar to John’s (a bare heel at birth), and Silver’s retelling mirrors Furlong in tone: “Confirmation that this was EB, confirmation that it was a severe subtype, and besides that [Silver bangs the table], we don’t know.” Like John, these early wounds have never fully healed for Jackson. Their heels, like Achilles, remain a constant symbol of their mere mortality. Unlike Achilles, it takes less effort to remind them of the misfortune.

Yet, Silver’s relationship with Collagen VII betrays his outlook: he thinks of it as an elusive holy grail, rather than a villain. He was not, and is not, satisfied with the therapeutic opportunities of the present, nor the prognostic damn-near-certainties of the future. Impetuous and inspired, Silver believes “the most important thing I could do was give my son a chance at a good life. I was going to get there, or I was going to die trying.”

As such, he set out to do more than “commiserate, holler and march.” He was not, and is not, satisfied with the model of the village that nourishes its own, hoping for change, wielding its voice only when so invited. As he put it, “running a charity from a ‘goodness of your heart’ perspective is not a robust strategy.”

EBRP is a nomadic clan at war, and Silver is its dogmatic chieftain. EBRP operates through a venture philanthropy model, a model that leverages his numerical talents and his numbing tenacity: raise money, invest it in preclinical research, optimize developmental prospects, and sell at a return. This is effectively a private-public partnership, with philanthropic entity as de-risking middleman.

In other words, Silver seeks to redefine charity: “nonprofit is a tax-advantaged revenue structure, not a business model.” He scoffed: “There’s a funny stigma, that nonprofits exist not to make a profit. That’s insane. They exist to make as much of a profit as possible, and to plow that back into their missions.” He fumed: “The nonprofit business model sucks. Yet people say it shouldn’t be done our way. Tell me why? Because it hasn’t? I think it’s the most inane answer. It needs to change.”

Make no mistake: disruption requires being disruptive. This motivated misbehavior may be even more indispensable in the nonprofit realm, given the calamities addressed. As Silver put it, since most EB patients live to no more than 30, “If we can accelerate development by three years, that’s 10 percent of life.”


Hesitation to adopt the venture philanthropy model emerges from the refrain against “having skin in the game.” Critics argue lopsided allocation of capital towards discrete causes is a violation of bioethical purity (disease disparities will mirror wealth disparities) and a contamination of experimental sterility (introduction of inextricable biases).

Tachi Yamada, former Health Principal at the Gates Foundation, disputes this stance. Dr. Yamada, divining with oracular insight, subdivides the notion of innovation into two distinctive principles: “that which is evolutionary, and that which is revolutionary.” Innovation by evolutionary means adhering to convention, eschewing “peerlessness in favor of peer review.” It is risk-averse, seeking projects with a high probability of success. It is non-radical and linear, the plodding procedure of the “fat and content.” Revolution, on the other hand, is instantaneous and parabolic, the raucous outburst of the displeased and deprived. It revokes convention in favor of invention. It is averse to the static, festering stench of process.

History invariably bears out the necessity of such conceptual violence. The word “coup,” — translated alternatively as “blow,” “jab,” “lash,” “slug,” “sock,” or “wallop” — hardly describes a gradual, civil progression. More likely than not, those spearheading the revolution have themselves felt victim to such systematic violence: coup d’soi precedes coup d’etat.

This sequence is dramatized by a pugilistic, emaciated Matthew McConaughey in “Dallas Buyers Club” (47). The Hollywood ending — true, in this case — was the FDA approval of azidothymidine (AZT) for treatment of HIV. AZT was the first drug developed under the auspices of the ODA. Upheaval is rarely instigated by the “comfortable.” Desperation is a nearly nuclear substrate to this end.

Dr. Yamada is neither surprised nor disturbed that, increasingly, “money comes from the true sufferers of the disease,” nor that they “put a disproportionate share in the diseases that most affect their future.” As he wrote in 2008, the highway towards the future is through “bold ideas — even wacky ones — [needing] just a little help getting tested.”(48). Dr. Yamada’s bets are on “little science” to seize the day (49).

Validating this approach, between 2000-2006, trials funded by nonprofit sources were 75 percent more likely to be published than those funded by industry alone (50). Having skin in the game is the most potent catalyst precipitating revolutionary change. For patients with EB, the idiom is more than a metaphor.


Most orphan diseases, however, lack a Silver or a McConaughey. As a result, they default their prospects of therapeutic salvation to pharmaceutical companies. There has long been a tenuous relationship between patients and pharma, which has come prominently to the fore through so deemed “price-gouging.” Recent examples are many: “pharma bro” Martin Shkreli’s price jacking of Daraprim 55 fold is a particularly nefarious case study (51). Patients’ distrust and disenfranchisement come with little wonder: the pursuit of profit can seem an exercise in profiteering.

But the issue is more complex than price tags. It better understood as disconnect on three dimensions: efficacy, effectiveness, and equity.

Efficacy denotes the ability of a drug to achieve statistical significance in preclinical experimental models. The frustration is that development of novel, useful molecules does not occur fast enough. A 1999 study indicated that only 1.3 percent of pharmaceutical revenues are devoted towards drug discovery, whereas 25 percent are committed to marketing; a pill “producing to pushing” ratio of one to nineteen (52-54). From 2006-2015, nine in 10 potential therapies failed clinical testing (55). Between 2007-2010, two-thirds of drugs progressing to phase-2 trials lacked any clinical efficacy whatsoever (56).

Next is the question of effectiveness. Effectiveness describes the ability of a drug to exhibit clinical significance — a trickier matter, not in least part, due to its subjectivity. Historically, some 85 percent of drugs do not exhibit “therapeutic gains” over existing treatments (57). In an analysis of a group of common medications, only 65 percent demonstrated any effectiveness (versus placebo) — 36 percent on the basis of surrogate markers, rather than symptom relief or more common clinical outcomes (58). Perhaps the crux of the effectiveness issue resides inexclusion criteria, which tightly control trial patient populations. The spectral uniqueness of individuals is suppressed beneath the monochromatic shading of study cohorts. Per Solomon, “In nature, variation is the only invariable.” (45)

Finally, equity relates to the ability of patients to access a given drug. The most common boundary to access is price. This is the most strained axis between patients and pharmas. Whereas the ODA was originally aimed at providing incentives to coax pharma interest, evidence now shows that orphan drugs are equivalent in economic value to non-orphan drugs (around 400 million apiece) (59). The average cost paid per patient for orphan drugs was $140,443 in 2016, or 28,300 tubes of Aquaphor from Walmart. In theory, orphan drugs should only consume 0.75 percent of therapeutic spend on account of disease burden. In reality, they consume multiples higher — and individual drugs, like Revatio, drain a skewed fraction of the spend (60-62).

Worth noting: Revatio is a reformulation of sildenafil, the active molecule in medications for erectile dysfunction. Per Silver: “Now that everyone can get Viagra, diseases like EB should be top of the pipeline.”


Nevertheless, one would be naïve to disregard the profound value pharmaceutical companies add to society. Ian Maitland wrote in 2002:

Whatever the public’s misgivings, it shows no signs of being willing to forgo the benefits of the market…The result is that drug makers are whipsawed between conflicting public expectations. On the one hand, they are expected to maintain the flow of new life-saving and life-enhancing medicines. On the other, they are exhorted to price their products “responsibly.” We rely on the profit motive to mobilize vast resources to fight disease, but we are shocked when new drugs earn ‘windfall’ profits. We enjoy the fruits of capitalism, but we expect firms to behave a little less capitalistically. (63)

Numerical support of pharma’s contributions are legion: $15 billion in drug expenditures yields $427 billion in increased productivity, and a $1 increase in drug spending saves three and a half times that on hospital costs annually (63). They have played a significant role in the seven-year increase in life expectancy since 1960 (at a cost of only $20,000 per year gained) (64).

Yet, vilification of the industry is easier than valuation and comes more naturally than valorization. Maitland says pharma has become a “pariah industry…the villains of contemporary populist folklore. The merchants of life, as it were, have become almost as reviled as the ‘merchants of death’ formerly were…victim[s] of [their] own success.” (63)

On its best days, orphan pharma might appear as described by Jayne Gershkowitz, chief patient advocate at Amicus: “A patient-centric business model, with integrity and patient focus, grounded in the notion that if we develop novel medicines that have a profound impact, then profits will follow.” Mantra: do well while doing good.

On its worst, orphan pharma might seem as embodied by Steven Bull, director of portfolio strategy at Recordati: an agent manipulating “a system in which most people never see the price,” and where the “majority of insurers cover the drug” regardless of price; a salesman that determines price “by tipping our toe in the water and seeing what the market will bear;” and a dealer that will “continue to exploit so long as government refuses to have difficult conversations.” Dr. Bull, who prefers conversations on his cell rather than his landline because he “likes to walk and talk,” personifies the underbelly of the oft-portrayed monster.


John LaMattina, former Pfizer executive, believes the plot is thicker: “The bottom line… is that the payers are the hurdle.” Within free markets, prices reflect value. Insurance companies must be the stewards of both our value and our values. The financial and moral buck must stop with them.

Indeed, payers are the last line of negotiation in the U.S. market. Yet payer decision-making is notoriously subjective. In a typifying article titled “I had a tough day today, Hillary”, the writer recounts a day of reimbursement decisions and decision-making. Internal biases and arbitrary considerations pervade the piece. Responders had a field day, inflamed with shock and sadness and awe that so many lives be left to the whims of a single party (65). In the U.S., this party is most frequently a profit-maximizing actor.

Other systems, such as the National Institute for Health and Care Excellence (NICE) in the U.K., are more quantitative. NICE determines reimbursement based on the incremental cost-effectiveness ratio (ICER) of a given intervention per quality-adjusted life year (QALY) gained by the intervention (66). Ideally, this comprehensively considers and properly weights the variables at play, from the input of the populace at large. Rationality, however “cold” it may seem (the major criticism of NICE), may be vital for a sustainable public health system.

Payers play judge and jury when it comes to healthcare coverage. One hopes the jury incorporates the input of peers and that the judge rules according to rational, objective criteria.


The three-part concoction of helplessness, confusion, and frustration for orphan disease patients in accessing potentially curative therapies — whether due to lack of development (at the level of research enterprise), lack of access (at the level of pricing), or lack of coverage (at the level of insurance) — has led to an implosion of faith in the healthcare system and an explosion of efforts to bypass it.

This has crystallized into the variously named “right to try,” “compassionate use,” and “expanded access” movements sweeping the country. Right to try legislation, implicitly blaming the FDA for bottlenecking the approval process, allows patients with diseases refractory to available therapies to appeal for access to non-approved pipeline drugs. Those in support, including Vice President Mike Pence, claim it “gives patients a fighting chance” by “circumventing the bureaucratic processes at the FDA.”(67, 68)

Aaron Kesselheim, Harvard internist, lawyer, and scholar, fundamentally disagrees. For starters, he cites that the FDA approves 99 percent of applications in end-stage circumstances. He went on, “Right to try movements are misguided — efforts driven by libertarian activists seeking to upend the pharmaceutical regulatory structure… and exploiting very sad cases to do that.” He says right to try bills are “generally useless” and “may be unconstitutional.”

Art Caplan, a prominent and vocal NYU bioethicist, was less tactful: “There’s nothing for patients at such early stages of research. If something did work, it would have to get published in a religious journal because it would be a miracle.”

Another incarnation of these animal spirits manifests through the 21st Century Cures Act. Part of the Act prioritizes surrogate biomarkers — biologic proxies — in the approval process. The EB example would be intracellular Collagen VII levels, a digit on a spreadsheet that may not correspond very well to John’s ability to tolerate mist from a showerhead.

The elevated importance of biomarkers acquired through patient registries and case series comes at the relative demotion of more traditional methodologies such as randomized controlled trials. The aim is to accelerate the process by enhanced evidentiary flexibility. The argument hails data, for its potential, over methodology, for its consistency.

Dr. Kesselheim’s response is perfectly captured in the title of his JAMA editorial, “New ‘21st Century Cures’ Legislation: Speed and Ease versus Science.” He notes that “the establishment decades ago of FDA standards… transformed the US pharmaceutical industry from purveyors of uncertain remedies into one of the most successful in the world.” (69) He believes abandonment of rigor for rapidity is myopic.

One of Dr. Kesselheim’s colleagues, Florence Bourgeois, worries for potential toxicity associated with a rush of unproven “remedies:” in a 2015 study evaluating agents for orphan cancers, only one-fifth showed evidence of clinical outcomes, whereas 97 percent had evidence of serious adverse events (70). The differentiation between snake oil and olive oil becomes difficult when the only endpoint assessed is whether they float in water. Per Caplan: “Disease can be coercive to patients. Hope is a potent elixir. In this case, it’s witch’s brew.”


Do we place our faith in speed or science, speculation or certainty, empiricism or pragmatism? One side sees government as a wise pair of spectacles over the shoulder. The other perceives a bumbling fool who cannot get out of his own way.

Distilled to their essence, these are constitutional (legislatively and morally) questions: of liberty versus libertarianism; of intervention versus interference; of protectionism versus paternalism. Resolution will require discourse and compromise, both of which take time. Unfortunately, time is the orphan patient’s scarcest resource.

Editor’s note: This post has been revised to clarify details. 

Read Part One and Part Three of this series.



Originally published: October 11, 2018
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