Cutting Time and Cost in the Clinical Drug Approval Process Cycle

In my readings about and discussions with cancer researchers, it is clear that the cost of bringing a new drug to market (almost one billion dollars) and the elapse time of 5 plus years at minimum is costing countless lives and untold billions of dollars. The following article printed in the WSJ on 10/2/10, "A New Rx for Medicine" caught my attention.

http://online.wsj.com/article/SB10001424052748703882404575520190576846812.html#articleTabs%3Darticle

The claim is that through personal genetic understanding and this novel approach to testing multiple drugs simultaneously, they can learn as much in 6 months as would be possible to learn in 5 years under current standard testing protocols. To me, this approach is a breakthrough. For ease of reference, the text of the article follows. Be forewarned, it is a long article, but well worth reading.

A New Rx for Medicine

Fed up with slow drug trials, cancer patients and doctors are testing a fast track to personalized treatments.

When 37-year-old Kerry Landreth discovered a lump in her breast last April, she was told it would take three weeks to get a doctor's appointment to have it checked.

"I don't do three weeks," she recalls saying. "How about today?"

By the end of the day, she had talked her way into a doctor's appointment, a mammogram and a biopsy to determine whether the suspicious lump was a tumor. A few days later came the diagnosis: stage 2 invasive ductal breast cancer, a particularly aggressive form of the disease. When a surgeon recommended a double mastectomy, she decided to consider other options.

Now, Ms. Landreth, a vice president at the San Francisco office of a Wall Street investment bank and the mother of two young children, is among the first participants in a novel clinical trial that is similarly impatient with the status quo in cancer treatment.

The trial, called I-Spy 2, employs several innovative approaches to improve the notoriously slow and inefficient process of developing new cancer drugs. Using the latest advances in genetics, I-Spy 2 aims to match experimental drugs with the molecular makeup of tumors most likely to respond to them. And it tests multiple drugs at once, with the intent of getting the most effective ones into late-stage trials more quickly.

The goal is to reverse a dismal record, in which 60% to 70% of late-stage cancer studies fail, and to dramatically reduce the time and cost required to get promising new drugs to the market. Currently it can take $1 billion, thousands of patients and more than a decade to gather the evidence necessary to approve a new cancer drug.

Kerry Landreth just finished her final round ofchemotherapy.

"Predictability is the Holy Grail here—being able to identify promising drug candidates early and figuring out who they might work in," says Janet Woodcock, director of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.

The new trial draws from a growing body of research showing that the genetic makeup of tumors varies widely even among patients diagnosed with the same cancer. Some of these molecular traits, called biomarkers, make a tumor vulnerable to a specific medicine, while others may thwart a drug's effect.
A big part of the problem with conventional trials is that they essentially take all comers. Researchers know many participants won't benefit from the treatment. Those who don't respond can cause a drug to fail even though a significant minority of patients might benefit.

"Unless we do something different, people are going to give up on doing trials" for cancer, says Laura Esserman, director of the breast-care center at University of California, San Francisco, and co-leader of I-Spy 2.

The study focuses on women with aggressive breast cancers that have not spread to other organs. It aims to collect information about experimental drugs that would then enable drug companies to design leaner, faster late-stage trials that enroll only patients whose tumors had a high probability of responding to the treatment. Those trials, called phase III trials, provide critical data used in determining whether a drug will be approved.
"The vision is a 300-patient phase III trial instead of a 3,000-patient trial, with better results," says Don Berry, head of Quantitative Sciences at M.D. Anderson Cancer Center in Houston and co-leader of the study.

I-Spy 2's effort to bring much higher standards of productivity to cancer-drug development is inspired partly by Dr. Esserman's experience at business school. In addition to her surgical training, she has an MBA from Stanford University, where she learned about the rapid pace of innovation in high-tech industries. She was particularly influenced by the idea of what Intel Corp. chairman Andrew Grove calls "knowledge turns"—breakthroughs that have led to annual advances in microchip technology and an ongoing revolution in the performance of products like personal computers.

In the development of cancer drugs, by contrast, "knowledge turns" may take 10 or 15 years. Typically treatments are first studied in metastatic patients—for whom cancer has spread from the original tumor site to other parts of the body—who didn't benefit from standard therapies. Even when drugs succeed, benefits often are limited to a few extra weeks or months of life. Then it takes several more years to test successful drugs in early-stage patients, for whom effective treatments could mean a cure.
"We have 45,000 women dying each year of breast cancer," Dr. Esserman says. "We should be compelled to move faster."

About 3½ years ago, she joined forces with Dr. Berry at M.D. Anderson, an expert in a new approach to clinical trials called "adaptive design," to plan I-Spy 2. Unlike conventional trials, in which no one sees results until the end, "we look at the data right away," Dr. Berry says. What is learned in the early going helps to determine which drugs are assigned to patients later in the study, speeding the emergence of winners and losers.

The trial incorporates other new approaches. It's currently testing five drugs at once from three different companies. As compounds graduate to phase III studies or are winnowed out for lack of significant benefit, new candidates are cycled in, sparing the cost and time to mount separate trials. Up to 12 candidates will be screened over the course of the study.

In addition, participants get a six-month course of chemotherapy before having an operation to remove their tumors. In many studies, surgery is performed first, followed by chemotherapy and radiation, reflecting a long-standing preference to quickly remove tumors before beginning drug treatment. As a result, it can take three to five years to determine whether a drug is working, as researchers wait to see if the cancer recurs. Whether surgery occurs before or after chemo does not affect long-term outcomes.

In I-Spy 2, researchers use an MRI to evaluate a tumor's response to a drug early in the trial and get a definitive answer at surgery. "All of a sudden I've taken a five-year learning curve and shortened it to six months," Dr. Esserman says.

Ms. Landreth's ordeal began with a heavy sensation in her left breast that led her to discover the lump. It seemed to come out of nowhere and felt as big and hard as a marble. The news that she had cancer came while she was on a business trip to Los Angeles. "It was a shocker," she says.
She didn't reject out of hand the surgeon's recommendation of a double mastectomy, but as she and her husband, Creighton Reed, cast a net among friends for advice, Dr. Esserman's name kept coming up. They were taken with her on their first meeting.

"She sweeps into the room like this Fleetwood Mac figure," Ms. Landreth says, referring to Dr. Esserman's resemblance to the group's singer Stevie Nicks. "There's no B.S. She cuts completely to the facts. She gives you a hug at the end. You leave thinking, 'All right, I can do this.'"

A key feature of the study is a molecular analysis that determines whether the participants' tumors are positive or negative for estrogen, progesterone and the Her2 protein—the basis for putting patients in one of 10 biomarker categories.

Every patient gets 12 weekly treatments with the standard chemotherapy taxol, followed by four biweekly infusions of the standard drugs Adriamycin and Cytoxan. A precursor study called I-Spy 1 showed that 30% of patients who got that regimen saw their tumors disappear completely.

About 80% of patients are also randomly assigned to one of five experimental agents (from Abbott Laboratories, Amgen Inc. and Pfizer Inc.), given with the taxol treatments. Each drug targets a different molecular pathway affecting the growth and proliferation of tumors.

Tumor response is assessed from MRIs and at the time of surgery after chemo is completed. The associations between tumor response and patient biomarkers among the early participants will influence how subsequent patients are assigned to the treatments.

"The goal is to pair drug and biomarker signatures and graduate them into a small phase III trial that has gotten rid of the subset of patients that don't benefit," says Dr. Berry.

There are challenges. Though biomarkers are a promising predictor of a drug's effectiveness, tumor response to a drug can vary widely despite biomarker status. Doctors say that more evidence is needed linking biomarkers to long-term outcomes.

Eric Winer, the director of breast oncology at Dana-Farber Cancer Institute in Boston, is not involved with I-Spy. He calls it "a very good trial," but he wonders if the bar is set too high. "We have to be very careful not to toss away drugs prematurely based on their failure to pass this screen," he says.

The bar is high, Dr. Esserman acknowledges, but the study isn't after incremental improvement. "This trial will say who are the big winners," she says.

Even if I-Spy 2 succeeds in showing that compounds have a high probability of success in small late-stage studies, it isn't clear yet whether or how the FDA's regulatory system would then enable faster drug approval. "That's our next step," Dr. Esserman says.

The study, to cost $25 million over five years, is sponsored by the Biomarkers Consortium, a public-private partnership managed by the Foundation for the National Institutes of Health. It includes representatives from the National Cancer Institute, the FDA and the pharmaceutical industry. Funders include the Safeway Foundation, UCSF, Quantum Leap Health Care Collaborative and several drug companies. So far, about 20 patients are enrolled, with the expectation that about 800 will participate at some 20 medical centers across the U.S.

Ms. Landreth was assigned to one of the experimental drugs and began treatment on May 18. By the second week, a physical check of her tumor suggested it had shrunk notably after just a single treatment. In one of what became weekly email updates to friends, she wrote: "I have always liked to get good grades, so the nerd in me was fully flourishing when the cancer nurse said she was 'over the moon' about how I'm responding to the drugs."

The next Tuesday, as she awaited her third round of chemo, she wrote: "I got in trouble with my chemo nurse for trying to tough it out this weekend. I didn't think that a 70 min walk, 18 holes of golf (I broke 100) and a little too much heat + a total failure to use the nausea drugs would cause a problem.... oops!" The result, she wrote, was almost unremitting vomiting for 36 hours.

But, she added, the tumor had shrunk dramatically again.

Later that week, an MRI confirmed the progress. After just three weeks, her tumor had shrunk more than 50%, a strong predictor, Dr. Esserman told her, that the tumor would be gone by the end of chemotherapy.
Still, the cumulative effect of the chemo exacted a toll on Ms. Landreth. She lost her hair, shaving it all off just days before her 37th birthday. Frequent nausea posed a persistent challenge to her energy and appetite. At one point, Hope Rugo, her oncologist, warned that she'd lost too much weight, information she disclosed in an update titled, "Bring on the guacamole."

By week eight, her tumor was the size of a watermelon seed, compared with a golf ball the day she enrolled. At week 12, it was the size of a sesame seed. Her medical team was ecstatic. "There's nothing like hearing them cheer," she says.

Not everyone sees tumors melt away. Inne Harry-Ogaree, 54, who entered the trial at about the same time as Ms. Landreth, had her tumor grow despite treatment with taxol and an experimental drug. She was switched to a more standard regimen, which has shrunk the tumor by more than 50%. "It hasn't been easy," Ms. Harry-Ogaree says. "But I have a positive attitude toward my treatment and my care."

Ms. Landreth's final chemo session was last Tuesday. Under the study protocol, she'll undergo surgery in November. The actual status of her tumor won't be known until then.

Three weeks into the trial, she got the results of a test for mutations in the BRCA1 and BRCA2 genes. Dr. Esserman suggested the test because of a family history of ovarian and prostate cancers. The test was positive for BRCA2, putting Ms. Landreth's lifetime risk of another bout with breast cancer as high as 85%; for ovarian cancer, it's 30%.

She knew immediately what her surgical plan would be: the double mastectomy that she had initially resisted. She plans to have her ovaries removed as well.

Ms. Landreth's results will go into the trial database and could affect which other patients are assigned to the drug. If it turns out, as Dr. Esserman expects, that her tumor is gone, she is unlikely to need radiation.
In her email update early this week, she expressed "high hopes" that surgery would reveal her to be "cancer-free." Reflecting both the challenge of the surgery ahead and the battle she has already fought, she wrote: "I have to remember that after 16 rounds of magic poison it is going to take awhile to bounce back, no matter how fierce my determination. Churchill apparently said, '[If] you are going through hell, keep going!'"

Write to Ron Winslow at ron.winslow@wsj.com