© ISTOCK.COM/RHUI 1979; SYLVERARTSIt was October 1988, and AIDS had reached epidemic proportions in the U.S. A crowd gathered in front of the US Food and Drug Administration (FDA) in Rockville, Maryland. “Forty-two thousand dead from AIDS,” the protestors chanted. “Where was the FDA?” The Centers for Disease Control and Prevention later concluded that more than 62,000 people in the U.S. had died from AIDS by the end of 1988.

The protestors, organized by the advocacy group ACT-UP, demanded that the FDA abandon placebo-group requirements in clinical studies testing AIDS drugs and radically speed access to any therapies that showed promise.

A week after the protest, the FDA announced that it would begin to consider approving drugs for life-threatening illnesses based on Phase 2 trial results. Drug companies could still be obligated to carry out additional trials after approval. Four years later, the agency added to this...

That same year, the FDA also launched a priority-review process, promising to review certain drugs in just 6 months and to limit standard review to 12 months (today’s standard review takes 10 months). While these expedited review programs were created in large part to address the AIDS crisis of the 1980s and ’90s, they have served to accelerate the development of cancer drugs, antimicrobials, rare genetic disease therapies, and more.

But AIDS activists and other disease advocates still weren’t satisfied, and continued to call for the FDA to support faster drug development. So in 1997, the FDA added another option—the fast-track designation, which allows drug developers to work closely with regulators and have portions of their applications considered before all components have been submitted. And just a few years ago, the agency introduced the breakthrough-therapy designation, which, in addition to rolling review, includes intensive guidance from the FDA’s senior management to plan the drug’s most efficient path to market. Together, these four designations transformed a once-plodding approval process to one that is currently among the fastest in the world.

Over time the application of these pathways broadens to encompass drugs that the pathways were maybe not intended to encompass.—Aaron Kesselheim,
Har­vard Medical School

“The vast majority of the time, the United States is the world’s first country to approve novel medicines,” the FDA wrote in an email to The Scientist. “In 2013, three-quarters of new drugs approved by the FDA were approved in the United States before any other country.” Nearly half of drugs approved that year were associated with one or more expedited-review programs (N Engl J Med, 370:e39, 2014).

But the accelerated review times have raised concerns that the FDA is becoming too lax, potentially approving drugs that could be more dangerous than helpful to patients. Indeed, some drugs that were approved under these expedited programs were pulled from the market after additional studies revealed they were unsafe or unhelpful.

Below, The Scientist examines the role expedited approval plays in drug development, and how drug companies are navigating the array of expedited options open to them.

Increasingly popular

The overall proportion of drugs receiving some type of special review status has risen by an average of 2.4 percent per year since 1987, according to a study published in the BMJ in September (351:h4633, 2015). In addition to the FDA’s accelerated-approval, priority-review, and fast-track programs, this study considered drugs reviewed under the FDA’s original program launched in 1988 immediately following the AIDS activists’ protest and those given orphan drug designation. This program was launched in 1983 to give the manufacturers of rare disease treatments tax breaks and lengthened market exclusivity. To some, this growth in the use of specialty pathways simply reflects a change in the focus of drug companies. “I believe it’s a reflection that the entire industry has gone so strongly towards orphan diseases and small specialty diseases,” says Ryan Million, a partner at the pharmaceutical consulting firm Trinity Partners in New York City.

To others, this is a sign that expedited-review programs have become bloated. “One possibility is the idea of designation creep,” says Aaron Kesselheim, who studies the effects of regulatory policies on drug development and approval at Harvard Medical School and Brigham and Women’s Hospital and co-authored the BMJ paper. “Over time . . . the application of these pathways broadens to encompass drugs that the pathways were maybe not intended to encompass.”

Kesselheim and his colleagues found that, despite the rise in expedited approvals, the number of first-in-class drugs—those first to use a given mechanism of action to treat a particular problem—stayed fairly flat, suggesting that non-innovative drugs are more likely now than before to enter expedited programs. “These expedited development and approval programs were intended for the cream of the crop of the drugs, and it certainly doesn’t seem like it’s being implemented in that way,” Kesselheim says. “I think that can waste resources and provide [positive] signals to patients about drugs that might not deserve them.”

Expediting approval of drugs may also increase the risk of a therapy that is unhelpful or, worse, unsafe for patients. For example, the FDA approved Wyeth’s (later Pfizer’s) antibody-drug conjugate Mylotarg to treat acute myeloid leukemia in 2000 based on promising Phase 2 trials. But in early 2009, a subsequent trial was halted because the drug did not appear to be any better than a standard chemotherapy regimen, and more patients died in the Mylotarg arm of the trial than in the standard chemotherapy arm. The following year, the agency pulled the treatment from the market.

Mylotarg’s issues may not be an isolated incident, with some studies indicating that faster approval times have come with increased postmarket safety problems (Health Aff, 33:81453-59, 2014). “There’s clear evidence that when reviews are done in half the time, it significantly increases the risks of hospitalization and death,” says Donald Light, professor of comparative health policy at Rowan University in Stratford, New Jersey.

Breaking through

Problems aside, the FDA’s expedited approval programs have benefited numerous companies and patients. The lion’s share of such approvals has gone to cancer therapies, which have made up 76 percent of priority reviews, 48 percent of fast-track designations, and 30 percent of accelerated approvals since the programs began, according to the BMJ study—larger shares of all of these programs than any other class of drug. And many for good reasons. Novartis’s tyrosine kinase inhibitor Gleevec, for example, was approved in 2001 after just two and a half months of review. The therapy eliminates symptoms and progression of chronic myeloid leukemia (CML) positive for  the Philadelphia chromosome, and it went on to win approval for multiple other cancers. Prior to the approval of Gleevec, just 30 percent of people with CML lived five years beyond initial diagnosis. In one trial focused on patients who took Gleevec consistently as their primary treatment, 89 percent lived five years or longer (N Engl J Med, 355:2408-17, 2006).

Many in industry and patient advocacy groups not only sing the praises of the agency’s expedited programs, but have continued to call for their expansion. In 2012, Congress and the FDA heeded the call. As part of the renewal of the Prescription Drug User Fee Act (PDUFA), which allows the FDA to collect fees from companies to help accelerate the drug-approval process, the agency introduced its fourth expedited program: the breakthrough-therapy designation. Unlike the accelerated-approval or priority-review programs, the breakthrough-therapy designation does not come with concrete changes to review length or drug-testing procedures. Instead, it promises increased opportunities to interact with regulators, including senior FDA management, starting early in the clinical trials process.

“FDA advice on a breakthrough-therapy-designated program can lead to the use of alternative clinical trial designs, such as an adaptive study design, or more efficient trials with small patient numbers,” representatives from Pfizer, which has three approved breakthrough drugs and two more in development, wrote in an email to The Scientist.

The advocacy group Friends of Cancer Research helped to spearhead the effort to develop the breakthrough-therapy designation. The creators of the new designation originally saw it as a pathway for a new generation of cancer drugs that targeted patients with specific genetic biomarkers or harnessed the power of the immune system. As a result of this narrow concept, Ellen Sigal, chairperson and founder of Friends of Cancer Research, guessed that maybe only a couple drugs per year would get the designation in early hearings. But the final wording of the designation’s requirements left it open to any therapies that “treat a serious or life-threatening disease or condition.”

“We had really no idea what this would mean,” says Sigal. But by the end of September 2015—a little over three years after the new designation’s launch—the FDA had received 337 breakthrough-therapy requests and granted 104 of them. In four cases, the FDA has rescinded breakthrough-therapy designations, and in two cases, sponsors have withdrawn their drugs from the program. According to records kept by the Friends of Cancer Research, the FDA has green-lighted 17 new drugs with the breakthrough-therapy designation and granted 18 additional approvals for novel indications.

The FDA has received 337 breakthrough-therapy requests and granted 104 of them.

Those in industry say the breakthrough therapy program is so popular because there is little downside to applying, as companies are not required to disclose whether or not they applied for the designation. Ariad Pharmaceuticals appears to be the only company to have publicly mentioned a breakthrough-therapy denial. The FDA rejected Ariad’s initial breakthrough application in 2013 for brigatinib, an experimental treatment for non-small cell lung cancer with an aberrant version of anaplastic lymphoma kinase (ALK). The company had presented results showing partial responses in 12 out of 16 patients with ALK-positive non-small cell lung cancer in its initial trial, as well as preliminary signs of improvement in some patients with brain metastases. But the FDA “wanted data from more patients,” says Andrew Slugg, vice president of regulatory affairs at Ariad.

Ariad resubmitted in 2014, showing that 26 out of 51 patients with ALK-positive lung cancer showed confirmed responses to brigatinib and confirming improvement in some patients with brain metastases. Ariad was also able to show how long patients responded to the drug. This time, the breakthrough application was accepted. Ariad expects to launch Phase 3 trials and file a new drug application this year.

Analysts say it is still too early to tell how the breakthrough-therapy designation is altering competition between drug companies. Consultant Million says it will depend on how evenly the FDA hands out breakthrough designations to drugs with competing indications. “If your competitors get [the breakthrough designation] and you don’t, I do think it’s problematic,” Million says. “Does that have an order-of-entry effect on you in the future? Is there some sort of signal that you’re negatively differentiated from your competitor?”

Navigating new waters

Novartis, which has already had two breakthrough therapies approved and has four more in development, has experienced firsthand the benefits of the new program. In 2014, the company received the breakthrough designation for a personalized cell therapy called CTL019, a chimeric antigen receptor T-cell (CAR-T) immunotherapy for the treatment of acute lymphoblastic leukemia. The treatment involves extracting T cells from patients’ own bodies and genetically modifying them to attack cancer cells. Robert Kowalski, senior vice president and global head of drug regulatory affairs at Novartis, says it has been helpful to consult with the FDA about how to obtain approval for the production process of CAR-T cells—a nontraditional drug product in that it involves introducing modified cells to patients.

In contrast, Novartis’s rare disease drug bimagrumab is relatively straightforward to manufacture. The monoclonal antibody stimulates muscle growth in people with sporadic inclusion body myositis (sIBM), a disease that causes muscles degeneration. For rare diseases, it’s valuable to discuss trial endpoints with the FDA ahead of time, as benchmarks for improvement have not yet been extensively validated. Kowalski also says that the publicity of receiving the breakthrough-therapy designation may have benefited bimagrumab. “We saw a higher awareness level for our clinical trials after we got the designation,” Kowalski says. “It basically tells the public that, hey, this is a really innovative, important compound.”

Emil Kakkis, president and founder of the EveryLife Foundation for Rare Diseases and chief executive officer of the rare disease–focused company Ultragenyx, says that he looks forward to expedited approvals for more rare-disease drugs. While the FDA’s cancer division has been very good at employing the agency’s expedited review programs, he says, “it’s been more uneven and less reliably utilized [for rare diseases].” As is the case with accelerated approvals, priority reviews, and fast-track designations, cancer therapies account for the greatest percentage (47 percent) of drugs that have received breakthrough status, according to Friends of Cancer Research; 16 percent target infectious diseases and only 12 percent target rare inherited disorders.

One important factor has been that cancer has well-established biomarkers that signify remission, making it easier to establish efficacy earlier in development. For each rare-disease drug, investigators are charting a fresh course. It can also be difficult to establish that a rare disease is truly serious, and whether a therapy improves quality of life sufficiently to count as a breakthrough, whereas cancer entails more obvious disease progression and threats on a patient’s life.

“You could argue it’s too fast or too easy” to get new drugs approved, says Kakkis. “I also argue that, at the pace we [have been] doing it, it will take hundreds of years to treat these diseases.” 

Designation Year enacted What it means Qualifications When to apply
Accelerated approval 1992 FDA approves the drug using a surrogate endpoint prior to Phase 3 results showing clinical benefit. (Phase 3 trials still must bear out the drug’s efficacy and safety after approval.) Drug must treat a “serious condition,” provide a “meaningful advantage over available therapy,” and have a measurable effect predictive of clinical benefit that can be measured earlier than final endpoints. During drug development, well before submitting a new drug application
Priority review 1992 The FDA reviews the new drug application within 6 months, rather than within 10 months. Drug must treat a “serious condition” and provide a “significant improvement in safety or effectiveness.” (Alternatively, companies can provide a priority review voucher, which allows a company to choose any drug to receive priority review. The FDA awarded vouchers to certain companies for developing drugs for tropical diseases and rare pediatric diseases. Companies have subsequently sold the vouchers to each other for as much as $350 million.) Submit with new drug application
Fast track 1997 Additional opportunities for interaction with the FDA; rolling review (drug company can submit parts of new drug application before whole application is complete) Drug must treat a “serious condition” and there must be some preclinical or clinical evidence that it has “the potential to address unmet medical need.” Submit with investigational new drug (IND) application at earliest
Breakthrough therapy 2012 FDA will provide “intensive guidance on efficient drug development” and will involve senior management to “expedite the development and review” of the therapy. The designation also comes with rolling review. Drug must treat a “serious condition” and clinical evidence must “demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies.” Sometime between the investigational new drug (IND) application and the end of Phase 2 trials

*Based on information the FDA provides in a more detailed table in the publication “Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics.”

Kate Yandell is a freelance science writer living in Philadelphia, Pennsylvania.

Correction (January 8): The original version of this story mistated that Ariad's Phase 3 trial would begin next year; the company plans to launch the trial in 2016. Also, there were 26 responders to brigatinib out of 51 patients, not 23 out of 57. The Scientist regrets the errors

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