In my most recent post on medicine approvals I explored how the HIV/AIDS crisis drove a reevaluation of what was truly essential to demonstrate a new drug’s efficacy. Allowing HIV patients to take investigational treatments meant that research into rarer conditions—which previously would never have been profitable—might now be financially worthwhile.
This post estimates the benefits of accelerated approval and how oncology medicines have become the treatment category with the most accelerated approvals.
Accelerated Approval Is Working, Especially for Cancer
Accelerated approval can facilitate the development of drugs indicated to treat rare diseases, many of which are forms of cancer. More than 25 million Americans suffer from rare diseases, which are particularly likely to be serious and life-threatening conditions with unmet medical needs. Of the 7,000 rare diseases that have been identified, more than 90% have no FDA-approved treatment.
Many facets of rare diseases make them particularly difficult to study in clinical trials targeting direct clinical benefit. It is widely acknowledged that developing drugs for rare diseases can be challenging due to characteristics like small heterogeneous patient populations, long timeframes for disease progression, a poor understanding of the disease’s natural history, and a lack of prior clinical studies. This makes accelerated approval a particularly important tool to develop treatments for these diseases.
And cancers—many of which affect only a few thousand people a year—have been targeted the most for accelerated approval. The reasons include a long-held attempt to combat cancer among scientists, past success in treating some cancers, a well-organized lobby to raise awareness and funds, drug companies that have spent decades combating the disease, and payers that were already accustomed to expending large sums for cancer treatments that cleared the U.S. Food and Drug Administration’s (FDA) regular approval process.
By the end of 2020, FDA had approved a total of 253 new drugs under the accelerated-approval pathway. From 1992 through roughly 2010, accelerated approval was primarily used to approve drugs indicated for treatment of HIV (39.7% of approvals); cancer (35.6%); and other rare disease treatments and specialty drugs (24.7%). Since then, the use of accelerated approval has shifted dramatically to focus on oncology drugs. Indeed, approximately 85% of accelerated approvals from 2010 to 2020 were for oncology indications.
Many of the additional approvals are for new indications for drugs previously approved to treat a different cancer. Keytruda is a major oncology drug developed by Merck and approved to treat multiple cancers, notably breast cancers. Naturally, given its impressive performance against myriad cancers, it has been tried against nearly all of them.
In some instances, its use to treat a new indication is withdrawn. For example, Keytruda was approved for gastric cancer treatment in September 2017 but accelerated approval was withdrawn in February 2022 when the drug didn’t appear to lead to a significant clinical benefit after confirmatory studies. This is the way the system is supposed to work. If a drug shows some promise, it is given early approval. But if this promise is not confirmed, the approval is withdrawn.
In total, 26 cancer approvals have been withdrawn for failing to demonstrate clinical benefit after confirmatory studies. Whereas 96 accelerated approvals to treat cancers have gone on to show undeniable clinical benefit. The remainder are still approved, with some clinical benefits shown, but to an uncertain extent and are still being investigated.
Over the past dozen years, during which time oncology medicines have dominated accelerated approvals, the median time from approval to withdrawal of approval was 3.5 years, and conversion from accelerated to regular approval took a median of 2.3 years.
Quantifying the Benefits of Accelerated Approval
To test the impact of accelerated approval, the industry-backed group Vital Transformations calculated the net present value (NPV) of 93 primary accelerated-approval therapies from 2001-2021 (drugs with at least one FDA-approved indication). An economic model was built testing the impacts of delays of two, three, four, and five years in the granting of full FDA marketing approval to determine the NPV of any accelerated-approval therapy.
For most of the orphan conditions currently lacking treatment in the United States, each condition affects at most 330 people—an incidence rate less than one in a million. Without the accelerated-approval pathway, the Vital Transformations research suggests that the potential development of these therapies to treat many rare diseases would be economically untenable. Vital Transformations estimated that:
- 33% to 66% of accelerated approvals at the median delay of three years would no longer have a net positive NPV, and a company may no longer invest in the therapy, or its development could be halted.
- 82% of accelerated approvals are for orphan indications; smaller confirmatory trials take longer to meet their FDA requirements; larger and faster confirmatory trials predict a positive NPV with statistical significance (p < 0.0004).
- Secondary indications appear to be a logical strategy to ensure an overall net positive NPV and help to retain drugs in the market, but genetically targeted therapies don’t have the opportunity for secondary indications.
- Gleevec, Opdivo, and Keytruda have had more than 50% of all secondary indications awarded, as they are highly effective late-stage treatments for cancer.
- There is a 63% probability that a therapeutically significant therapy (blockbuster) was created by a small company (annual revenue of less than $500 million); more than 80% of small IP-producing companies are based in the United States.
- 85% of untreated orphan indications have incidence rates of less than 1/1,000,000; changes to the accelerated-approval pathway would render the development of those therapies economically untenable.
- Slowing the accelerated-approval pathway will lead to therapies leaving or not coming to market; these at-risk therapies cumulatively address the needs of 850,000 to 3.6 million patients, depending on cost assumptions and estimated delay time.
As the authors told me: “If removing accelerated approval leads to a five-year delay, the percentage of therapies with a negative NPV would rise to between 51% and 73%.”
As will be discussed in more detail in a later post, some firms may not be doing their statutorily required confirmatory studies in a timely fashion. But Vital Transformations suggests that 80% of confirmatory trials are filed within five years as follow-up to accelerated approval. The smaller the population of the diseases, the longer it takes to find participants. Hence, it is harder to complete a trial and some fail to fulfill within the requisite time.
But the authors noted that this does not mean that these are “bad actors”; just that the company is trying to solve a really difficult problem for very few people. It is a “logical pattern of behavior” and “predictable that trials for small populations take longer.” These are less likely to be “profitable drugs,” so it is not in the companies’ favor to delay trials.
Vital Transformations’ arguments may constitute an overly positive gloss on the benefits of accelerated approval, but it is undeniable that there have been benefits. The current pathway has led to the approval of many drugs that have helped patients.
For example, according to Adam Brufsky, clinical oncologist at Pittsburgh Medical Center, at least two types of medicines—especially CDK46 inhibitors and trastuzumab-dexruxtecan (Herceptin), which were both approved under accelerated approval—have been remarkable at treating breast cancer. Brufsky told me that accelerated approved drugs have improved the lives of hundreds of thousands, maybe millions, of women since they were first approved in 1998. Furthermore, breast-cancer patients (and their support networks) know that, when they fail to respond to one treatment, the disease progression can be rapid, so fast approvals and the right to try pending drugs is high on their list of priorities.
Brufsky’s insights lead to further understanding of why cancer medications are the type most approved rapidly. Cancer can progress rapidly and new treatments are constantly required. This is true across many types of cancer and, as such, the entire support network of cancer advocacy pushes rapid approval of new and exciting medicines.
As a result, oncologists are likely more familiar with these medicines than regular physicians. To find out how familiar, I decided to interview oncologists about their prescribing practices, to see how many had knowingly prescribed accelerated products. This is an ongoing survey, which will be published later, but some of the more general responses are discussed briefly below.
Summary Survey Results
Of 131 oncologists approached to participate in a brief survey, more than three quarters (104) responded in full to the questions posed.
Within the previous five years, 78% (79 of 104) oncologists have prescribed a medicine that was approved through accelerated access, and only 19% said they were fairly sure they had not. Additionally, 62% had prescribed a medicine “off-label” (not for FDA-approved intent) in the last five years. Perhaps more importantly, 25% said there were medicines they had read about, and/or were in trials, that they wished they could try for certain patients.
Also roughly two-thirds (65%) thought that medicines should be available for them to prescribe if they had received accelerated approval, and not just be allowed for use in clinical trials, or in very restrictive ways (as is the case with some approvals). As one put it “real world clinical feedback can be just as useful as clinical trial data, and it should be for my patient and I to decide whether a drug is taken…not insurers or payers.” Furthermore, 75% of oncologists didn’t prescribe at least one medication they otherwise would because of cost. They knew their patient couldn’t afford it and most, presumably, had insurance coverage or were on Medicare.
All oncologists who ventured an opinion saw a role for the FDA in approving and regulating medicines, with only 6% thinking clinical-trial data—even peer-reviewed data from pharmaceutical companies—were sufficiently reliable without FDA oversight.
But there was concern among many physicians (75%) who thought that the FDA was too slow in approving new medicines. As two physicians put it to me, they are specialists in a disease area—those seeing patients and often at the cutting edge of research—and felt they could evaluate trial data and decide on a case-by-case basis whether a patient could use an unproved medicine. And while they relied on the FDA to assess overall data, they felt they should be deciding whether to prescribe a medicine.
I broadened the discussion to the idea of rapid “challenge” trials, with small numbers of participants, and hence cheaper and faster than current trials. Nearly three-quarters of oncologists thought rapid trials a good idea where no treatment exists for extremely sick patients. For at least a third, frustration is high that patients die while waiting for long-term trial results.
I will return to this ongoing survey in future posts.
Overall, while there is frustration among surveyed oncologists that approvals are not quicker, there is no doubt that the accelerated-approval process has been a boon to those developing, prescribing, and taking oncology medicines.