As well as big business, it is a saga full of celebrities and drama, framed by truly heart-wrenching stories and featuring calls for what then-Vice President Joe Biden called a cancer “moonshot” after his son Beau passed away in 2015. Although efforts to declare “war on cancer” go back to the Nixon administration, they have yielded less than one might expect. The overall death rate from cancer has fallen only 5 percent since 1950, which some attribute primarily to the decline in smoking since the 1990s rather than research. And new cancer drugs approved between 2003 and 2013 increased overall survival by an average of only 3.4 months. So much money and energy has been directed toward developing cancer drugs targeting rare, specific cancers — certainly benefiting individual patients and some types of cancer — but overall survival rates have barely budged. Why?
Curing cancer is an enormously difficult technical and medical problem. But despite periodic pleas to eradicate cancer, the federal government hasn’t actually invested large sums or directed researchers to focus on cancer. What we are seeing from pharma isn’t a concerted effort to cure cancer, but a piecemeal response to a regulatory regime that has encouraged quantity over quality.
At the heart of this history is the “orphan drug” designation. Originally passed in 1983, the Orphan Drug Act was designed to provide incentives for drug development when companies have “no reasonable expectation that the cost of developing … will be recovered.” In other words, the idea was to incentivize companies to develop drugs to tackle rare diseases, when there would be no hope of turning a profit and therefore no financial reason to develop a drug.
The legislation brought a host of benefits to pharmaceutical companies, the most valuable being a seven-year marketing right. During the seven-year period, the Food and Drug Administration doesn’t grant any other company approval to market the same drug for the same orphan designation, even if the drug’s patents have expired or are held invalid. Thus, orphan drug designations can help companies dominate the market on certain drugs without investing nearly as much into research and development as it would take to create all-new medicines.
Passage of the orphan drug program depended on dramatic rhetoric and heart-rending storytelling. The hearings featured a Hollywood star reenacting a poignant dramatization. The popular television show “Quincy, M.E.” had featured an episode about the plight of a patient with a rare disease, including a scene of testimony before a fictitious Congress. Jack Klugman, beloved star of the show, reenacted that moment — providing actual congressional testimony in support of the Orphan Drug Act.
Even the name Orphan Drug Act reflected drama, conjuring up the image of abandoned and neglected children. It was a brilliant strategic choice that made it difficult for anyone in Congress to oppose the idea. That rhetoric continues to this day with industry sources using language that sounds as if the diseases are neighborhood mafia dons: Rare diseases are described as “tragically killing and brutalizing mostly children.”
Despite the benefits to drug companies, the industry response to the Orphan Drug Act was tepid. So Congress amended it in 1984 to include a simple litmus test. If a disease affected fewer than 200,000 people, a company could enjoy the benefits of the Orphan Drug Act. That number, 200,000, was not the product of thoughtful economic and scientific analysis, however. It was chosen to make sure the legislation covered two particular drugs. One treated narcolepsy, and the other treated multiple sclerosis; neither involved cancer.
With that change, however, the program took off like wildfire. Pharmaceutical companies began investing in drugs that would fit the new definition, assured that they would enjoy seven years of exclusivity, tax credits and expedited approvals.
People with rare diseases — especially cancer — are often desperate for treatments, and drug companies have discovered that for orphan drugs, the sky’s the limit on pricing, particularly when the government is keeping competitors away. As a result, the costs to consumers and insurers are staggering.
Orphan drug designation has become associated with large-dollar returns. In fact, out of the 10 drugs with the highest annual sales revenue in 2015, seven were orphan drugs. Some drugs that receive orphan designations are indeed the product of expensive research targeted at solving rare diseases. But orphan drug benefits can go to drugs that already exist, are merely recycled, or that were developed for rare uses and became blockbuster drugs for large populations. The original goal of the act — to provide support when there is no reasonable expectation of recovering the cost of research — has been lost in the stampede.
Changing the Orphan Drug Act’s gateway to a defined number, along with modern medical techniques that focus on genetic markers and variations, also set the stage for the industry’s shift to focusing on cancer drugs. With advances in precision medicine, cancer treatments can be described in terms of small, targeted populations so that treating each of those populations can lead to multiple orphan drug designations.
While the orphan indication has redirected investment into drugs that have proved lifesaving for some, this policy has actually directed funds away from diseases and conditions that affect far larger numbers of people. Of all the novel drug therapies that gained FDA approval last year, more than half had an orphan indication. It would be a strange world, indeed, if we intended to direct more than half of our energy into treating diseases that affect small numbers of people.
There are many other ways that the regulatory system directs industry toward cancer in an ad hoc manner. The clinical trial approval process, for example, is easier for cancer drugs than for other drugs — companies can enroll fewer patients and can use substitute endpoints, rather than actual results. Comparatively, the FDA makes life more difficult for non-cancer drugs — disincentivizing investment in other health-care needs that affect large numbers of people, such as birth control and antibiotics. In particular, despite concerns about the rise of drug-resistant bacteria — including a British report anticipating 10 million deaths a year by 2050 — research in the antibiotics space is declining.
At the moment, it appears that the regulatory programs that have directed focus to cancer drugs incentivize torrents of activity with disappointingly minimal effects on extending the quality and quantity of life. There have been wonderful successes for individual patients, as well as substantial progress in treatment for particular types of cancer, such as breast cancer and Hodgkin’s lymphoma. But the overall death rate from cancer has barely budged since 1950.
The big question is whether the societal focus on cancer is beneficial, particularly considering that the outcome driven by our regulatory scheme developed in a manner unintended in scope or direction. These efforts could be tiny steps along the path of eventual success, but no budget is limitless, and no health-care system can engage in a cancer moonshot without diverting energy from other health goals. When engaging in a moonshot, it is best to do so with one’s eyes open, given that flying blind is a marvelous way to crash and burn. The greatest risk is not only that our moonshot may fail, but that the nation’s other public health needs will be left in the dust.