Trial design, clinician advocacy key to acceleration of research, review processes

The time required for an investigational treatment to move from clinical trials through FDA review is understandably lengthy due to the planning, peer review and quality control necessary to ensure efficacy and safety.

Moore and colleagues examined the development times of the 20 therapeutic drugs that received FDA approval in 2008. The results, published in October 2013 in JAMA Internal Medicine, showed the 12 drugs that underwent standard FDA review required a median 7.5 years (range, 4.7-19.4) of clinical development to obtain marketing approval. The eight drugs that underwent expedited review required a median 5.1 years (range, 1.6-10.6 years) of development to obtain marketing approval.

Clinicians and researchers in the hematology and oncology communities have called for renewed focus on efforts to streamline this process. ASCO also released a report offering its recommendations to accelerate the time in which laboratory discoveries are translated into life-saving therapies.

“ASCO has sought to address a number of factors involved in clinical trials and study design,” Neal Meropol, MD, division chief of hematology and oncology, at University Hospitals Case Medical Center, director of clinical research at Case Comprehensive Cancer Center at Case Western Reserve University and one of the executive editors of the ASCO report, told HemOnc Today. “We wanted to look at how we can better design studies so they will be smarter and faster to complete.”

Several factors contribute to the length of the process, including the fact that it encompasses four distinct stages: planning, patient accrual, the study period and FDA review.

HemOnc Today spoke with several key opinion leaders about how each of those steps may be modified, as well as the role other factors such as obstacles to patient participation in clinical trials, regulatory requirements and advances in technology could have on those efforts.

The timeline

The first challenge in the clinical research process is to secure funding. Subsequent steps — including development of concept, approval of concept, writing protocols, approval of protocols from the funding agency, and initiation of a contract with the funding agency — each can take several months.

This often means 1 or 2 years elapse before patient accrual begins. Once study data mature, it can become a candidate for publication. That requires months or even years of revisions and edits.

“All of this adds up to an average of 4 to 6 years from study concept to publication,” said Sikander Ailawadhi, MD, assistant professor of medicine and assistant medical director of the Clinical Investigations Support Office at USC Norris Comprehensive Cancer Center.

This delay may come with clinical consequences.

“Sometimes, by the time the data are mature and published, the results may no longer be relevant, or the drug’s efficacy or safety has been proven or disproven,” Ailawadhi told HemOnc Today. “When the study was designed, it was an appropriate question, but by time the study comes out, it is no longer appropriate. Everything is a moving target.”

Once data from multiple early-stage trials emerge, researchers must prove the therapy under investigation can match or improve upon the current standard of care. The process essentially starts over, and results of advanced trials set the stage for an FDA review that can take several months or even years.

“Much of this is unavoidable,” Ailawadhi said. “Also, when you factor all of the unsuccessful studies registered and underway on clinicaltrials.gov, it is understandable that the FDA takes so much time. So many studies are open and accruing but are not resulting in clear answers.”

Recent advances in cancer treatment also are a factor, Ailawadhi said.

“Our drugs are getting better and better,” he said. “But what happens, then, is we need to do much larger studies to show much smaller improvement.”

ASCO blueprint

Several specific suggestions have been offered to accelerate therapy development.

The most comprehensive outline came in the report, “Accelerating progress against cancer: ASCO’s blueprint for transforming clinical and translational clinical research.” The document outlines the society’s vision for faster development of effective, personalized cancer treatments.

The report suggests the clinical cancer research system in the United States is hampered by several factors:

• Regulatory and financial barriers limit the abilities of researchers and industry to collaborate on new approaches.
• Trial designs are not flexible enough to rapidly provide information about the safety or effectiveness of treatments in specific molecularly defined subsets of patients.
• Regulatory requirements and research funding cuts have weakened the clinical trial system.

The report offered several “real-world recommendations” to design faster, smarter clinical trials and make cancer research more efficient, targeted and effective.

They include:

• Prioritize trials with the most potential to benefit patients or that address clear unmet needs.
• Develop standards for flexible trial designs through which researchers can demonstrate a therapy’s effectiveness in smaller patient populations with specific molecular characteristics.
• Choose trial participants based primarily on molecular characteristics to ensure only those most likely to benefit are included.

The report also encouraged standardization of oncology electronic health records. Information should have a consistent format and contain all essential information, ranging from tumor biology to the site where treatment is administered. All clinicians also should be able to view relevant clinical trial information and share patient data in secure Web-based and mobile formats. Outcomes should be documented using universal language and accessible to everyone involved in the patient’s care.

“With the recent explosion in our scientific knowledge about cancer, we can finally begin to solve some of the toughest challenges in cancer care,” Michael P. Link, MD, former ASCO president, and service chief of pediatric hematology-oncology and Lydia J. Lee professor in pediatric oncology at Lucile Packard Children’s Hospital at Stanford, said when the report was released. “We could begin to see major progress in treating even the most difficult cancers — but the speed with which we do this is dependent on modernizing the nation’s cancer research system for the molecular era.”

Strategies in place

Several strategies are in place to try to streamline the research and approval processes.

“There are templates to follow for writing protocols that make things easier,” Ailawadhi said. “If it’s a clean concept that follows the rules, it is easier and faster to get funded and ratified.”

Researchers also have ways to informally approach NCI to determine the potential success of a study or whether it will be redundant.

“This can help shorten the timelines,” Ailawadhi said. “The NCI has approval processes, so we eliminate those steps from our process to avoid redundancy. The truth is nobody wants to do a bad study or a study that will fail or harm patients, so everybody wants to put up safeguards.”

Some efforts already are paying dividends.

The NCI convened the Operational Efficiency Working Group in 2008 to develop recommendations to decrease the time with which NCI-sponsored clinical trials progress from the conceptual stage to patient enrollment.

The group established protocols designed to help all stakeholders in clinical research streamline their processes. Components included new staff positions to monitor progress, creation of websites to track protocols and use of strategically planned conference calls.

The group also established target timelines — 7 months for phase 1 and 2 studies, and 10 months for phase 3 studies — as well as absolute deadlines of 18 months for phase 1 and 2 studies and 24 months for phase 3 studies.

Initial results, published in June 2013 in the Journal of the National Cancer Institute, showed development times for phase 1 and 2 studies decreased from a median 541 days to 442 days, an 18.3% decline. The development time for phase 3 studies declined from a median 727 days to 395 days, a 45.7% decline.

Patient accrual

Another component of the process that can be modified is the rate of patient participation in clinical trials.

“Accrual to clinical trials remains a critical concern,” Meropol said. “Unfortunately, only a small minority of cancer patients in the United States — about 5% or less, according to most estimates — participate in clinical trials. This is a major impediment to progress.”

Obstacles exist at the patient, physician, trial design and health care system levels.

“From the patient standpoint, a lack of awareness of clinical trials exists,” Meropol said. “More problematic is the fact that attitudes can impede patient willingness to consider participation.”

Those attitudes primarily revolve around misconceptions about the safety or quality of novel therapies, Meropol said. Patients often are concerned that they will receive a placebo, or be treated with an unsafe or inferior drug.

“Our survey work has told us that the biggest barrier to participation is the fear of side effects,” Meropol said. “The reality is that side effects are no more common in a clinical trial than in standard therapy, and in many cases, the side effects are less.”

Alex Adjei, MD, PhD, FACP, senior vice president of clinical research and chair of the department of medicine at Roswell Park Cancer Institute, stated the concern more directly.

“People don’t want to be guinea pigs for a dummy drug,” Adjei said. “They think they are not going to get better if they are not given the standard of care. What they should understand is that we wouldn’t be studying a new drug if the standard of care was perfect.”

Many patients also fail to realize that placebo almost never will be administered alone, Meropol said.

“This is a myth about cancer clinical trials,” he said. “The vast majority of studies look at standard therapy plus placebo vs. standard plus new drug.”

Patients must understand that all treatments considered to be standard today once were viewed as experimental, Meropol said.

“We need to remind both clinicians and patients that a clinical trial represents the highest quality cancer care,” he said.

Too much bureaucracy, not enough awareness

In some ways, concerns about novel therapies are magnified due to regulatory requirements, Ailawadhi said.

“The informed consent forms in a clinical trial lay out every side effect for anyone who has ever taken that drug,” he said. “Patients read that and decide they do not want to subject themselves to those side effects. When you go over treatment with other standard therapies, clinicians don’t talk about side effects in such an exhaustive way. This creates misperceptions within the patient’s mind, the support staff’s mind and even in the clinician’s mind.”

Richard A. Larson, MD, professor of medicine in the section of hematology/oncology and director of the hematologic malignancies clinical research program at the University of Chicago, elaborated on this point.

“Informed consent is cumbersome,” Larson said. “Patients interested in a trial might be put off by a 20- or 25-page informed consent form. It can add to the complexity of a trial, and to the expense.”

The bureaucracy can have clinical implications, Ailawadhi said.

“The insurance approval and even the informed consent procedures or study screening procedures may delay the treatment,” he said. “From the practitioner’s standpoint, this delay may not be much, but patients want treatment right away. To a patient, any delay is too long.”

Lack of awareness also can limit patient accrual.

“Most patients receive care in community settings, where there often is less information available about clinical trials than at major cancer centers,” Meropol said.

With support from a grant from the NCI, Meropol has developed online educational tools to provide patients with tailored information about clinical trials and be better prepared to consider them as a treatment option.

“We’ve demonstrated that we can improve patient knowledge and attitudes about clinical trials, but a multipronged attack is needed if we are going to move the needle in increasing enrollment,” Meropol said.

Another barrier to accrual — the failure of those in the clinical community to encourage patients to enroll on trials — can easily be rectified, experts said.

“Unfortunately, sometimes the misperceptions among physicians are similar to the ones we see among patients,” Adjei said. “The problem in the clinical community is also a bureaucratic one. The sheer number of forms required for enrollment can be off-putting. Many physicians don’t want to deal with all of this.”

Larson offered a potential solution to that problem.

“Incentives have to be in place for physicians to refer patients to trials,” he said. “Also, incentives have to be in place for patients to drive 50 miles to get to a center to be on a clinical trial. We need to be encouraging this at all levels.”

Study design

ASCO has sought to address study design issues in its blueprint statement, Meropol said.

“One of those methods is adaptive study design,” he said. “If we can review results in real time as the study is underway, we can see when a potential new treatment is not working earlier, and shut it down.”

For example, if one arm of a three-arm study looks less promising, it should be possible to shift randomization to accrue patients to an arm in which the outcomes appear more promising.

A significant impediment to adaptive design is the requirement that a statistician is intimately involved with progress and monitoring of the study, Meropol said.

“This would not be a conceptual objective to the idea of adaptive design, but a practical issue that could limit widespread dissemination,” he said. “It may be problematic to have a statistician available for every step of a clinical trial.”

Adaptive trial designs offer tremendous promise for reducing development times of cancer drugs, and they also can help better identify responder patient populations, Donald A. Berry, MD, of The University of Texas MD Anderson Cancer Center, wrote in an editorial published in 2011 in the Journal of Clinical Oncology.

Adaptive randomization may be most effective in multi-armed trials that involve a number of clinical questions, Berry said. However, the utility of such designs may be limited to trials with two arms, a fixed sample size or no biomarkers.

“Any trial design should be evaluated on its merits and compared with other possible designs,” he wrote. “Adaptive trials are more complicated to build and to run than are conventional trials. They come with a number of downsides that should be assessed in the context of the positive aspects.”

Appropriate endpoints also must be considered, according to Maha Hussain, MD, FACP, professor of medical oncology, associate director for clinical research and co-leader of the prostate cancer/genitourinary oncology program at the University of Michigan Comprehensive Cancer Center.

“Actively pursuing validation of relevant intermediate and surrogate endpoints for clinically meaningful benefits can shorten the wait time for survival,” said Hussain, a HemOnc Today Editorial Board member.

The issue comes down to how the study is written, Ailawadhi said.

“Everyone wants to have a study that answers every question possible, but that’s not realistic,” he said. “It is better to ask a specific question and answer it thoroughly.”

The current culture dictates acquiring as much information as possible, Ailawadhi said. However, this may conflict with efforts to increase patient participation.

“Patients often will not want to undergo all of these biopsies, blood tests, CT scans and other procedures,” he said. “If a study is not patient-friendly, then it is going to drive them away. Clinicians also may be overwhelmed by the amount of work required.”

Next-gen sequencing

Clinicians disagree about the effects next-generation sequencing will have on the clinical research timeline.

Screening methods based on genetic information may yield more effective studies, Meropol said.

“Our current understanding of cancer biology and targets for cancer therapy are enabling us to design studies that are restricted to patients for whom the new drug is most likely to work,” Meropol said. “Not only will we be identifying more effective treatments, but we will need fewer patients to show that new treatments will actually work. They will work better in selective populations than in an all-comers design. This may accelerate progress.”

Genetic screening may have unintended consequences that slow the trial process, Larson said.

“There are about 10,000 cases of AML diagnosed per year in the United States,” Larson said. “If only 10% have the specific mutation you are targeting, you are down to 1,000 patients. Spread across 50 states, that is about 20 per state. Then your testing centers have to open a protocol to accrue those patients. With the IRB review process, it may not be worth effort if you are only going to accrue one or two patients a year for these orphan diseases. This may become even more difficult as small subsets become more specific.”

A study design with such a specific focus also may eliminate serendipity in research, Larson said.

“I worry that by focusing too narrowly on one target, you may actually miss targets that were not imagined,” he said. “In short, we may be expecting too much of next-generation sequencing. Targeting pathways that are ubiquitous to progression of particular tumors may provide a more generalizable therapy”

Adjei said he agrees with this to an extent.

“Genetic sequencing only looks at a small piece of the pie, but there are a lot of other factors that go into identifying targets,” he said. “Sequencing will help in some instances, but not all. It will take a long time to get to the point where we can find specific targets in all cancers.”

Approval process

The FDA has made strides in terms of fast-tracking promising therapies that seem to offer unique benefit to certain populations, experts said.

However, even this is no easy task, Ailawadhi said.

“The FDA is not charged with looking at just one study,” he said. “Gathering and analyzing all the data on a particular drug or indication is a huge undertaking.”

The potential for postmarketing redaction complicates matters.

“Nobody wants to rush into drug approval,” Ailawadhi said. “We have had examples of drugs getting approved, but then postmarketing data show safety issues or that the clinical benefit was not as great as initially considered.”

The FDA will grant approval based on phase 2 data if it is compelling, but it will still require a postmarketing study to validate the approval.

“Streamlined processes may become more important if you can get approval based on 50 patients having a better-than-expected response to new agent,” Larson said. “This brings us back to issue of slicing uncommon cancers into smaller pieces.”

The primary complicating factor associated with the FDA approval process is the off-label use of cancer therapies.

“Because there is always one more drug on the shelf to try ‘off-label,’ patients with relapsed or refractory disease are often kept in the community too long before being referred for investigational agents on clinical trials,” Larson said.

Ailawadhi said it may be helpful to look to other parts of the world to identify ways to streamline the approval process and other aspects of the research timeline.

“We see what is happening in places with socialized vs. non-socialized medicine,” he said. “Drugs get approved faster in Europe just because of the way health care systems are set up. Studies there are faster and larger, with more participation.”

Meropol suggested that regulatory requirements in other parts of world might not be as onerous as they are in the United States.

“Patients in other parts of the world also may not have as many standard treatment options available,” he said. “Therefore, a clinical trial is the only way they can get access to a particular treatment.”

Studies in the United States also are expensive, Meropol said.

“A high level of volunteerism by physicians is required to conduct publicly funded studies in the United States,” he said. “This can negatively impact speed of accrual and completion.”

Larson said he remains hopeful that the Affordable Care Act will increase participation in clinical trials.

“However, it remains to be seen whether accountable care organizations will provide the kind of incentives needed to speed up the whole process,” he said. — by Rob Volansky

References:

Abrams JS. J Natl Cancer Inst. 2013;doi:10.1093/jnci/djt137.

ASCO. Accelerating progress against cancer: ASCO’s blueprint for transforming clinical and translational clinical research. 2011. Available at: www.asco.org/sites/default/files/blueprint.pdf. Accessed on Dec. 4, 2013.

Berry DA. J Clin Oncol. 2011;29:606-609.

Moore TJ. JAMA Intern Med. 2013;doi:10.1001/jamainternmed.2013.11813.

For more information:

Alex Adjei, MD, PhD, FACP, can be reached at Roswell Park Cancer Institute, Elm and Carlton streets, Buffalo, NY 14263; email: alex.adjei@roswellpark.org.

Sikander Ailawadhi, MD, can be reached at University of Southern California, Norris Comprehensive Cancer Center 1441 Eastlake Ave., Los Angeles, CA 14263; email: ailawadh@usc.edu.

Maha Hussain, MD, FACP, can be reached at University of Michigan Medical Center, 7314 Cancer Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5946; email: mahahuss@med.umich.edu.

Richard A. Larson, MD, can be reached at The University of Chicago Medicine, 5841 S. Maryland Ave., Chicago, IL 60637; email: rlarson@medicine.bsd.uchicago.edu.

Neal Meropol, MD, can be reached at UH Case Medical Center, Department of Medicine — Hematology and Oncology, 11100 Euclid Ave., Cleveland, OH 44106; email: neal.meropol@case.edu.

Disclosure: Adjei, Ailawadhi, Hussain, Larson and Meropol report no relevant financial disclosures.

 

 

Can the FDA streamline the approval process?

Yes, the approval process can be streamlined.

The FDA already has made an important step by creating the new breakthrough therapy designation, through which nearly two dozen drugs are currently being developed (Sherman RE. N Engl J Med. 2013;369:1877-1880).

The recent approval of ibrutinib (Imbruvica; Pharmacyclics, Janssen) for three hematologic malignancies through this pathway shows the benefit of this mechanism is more than just theory.

The FDA previously utilized accelerated approval and priority review to decrease time to approval. These designations allow approval based upon surrogate endpoints or shortened review deadlines, respectively, but do not involve active engagement with the FDA.

The recent addition of the fast track and the breakthrough therapy designations represents an important step toward decreasing the time and expense associated with developing drugs. Most importantly, patients with serious diseases have quicker access to improved therapies.

The breakthrough therapy designation expedites the very early discussions between the FDA and the pharmaceutical or biotechnology companies on the appropriate patients, endpoints and trial designs. There must be a realization of the importance of cooperation between these groups early in the drug development process to prevent delays in approval due to educated, but incorrect, guesses by drug companies on what endpoints or trial designs the FDA will expect in order to gain drug approval.

Having shown that this process is effective with the current drugs in development, there is little reason to not consider expansion of this cooperation more broadly, particularly for serious diseases or diseases with unmet need. This may be a costly venture, but ultimately it prevents continued use of inadequate therapies for patients with these diseases. Continuing to treat patients with ineffective therapies when better ones may be available isn’t clinically or financial responsible and justifies the effort and expense required to continue improving the FDA’s drug approval process.

Dale R. Shepard, MD, PhD, is a staff physician in the department of solid tumor oncology at Cleveland Clinic’s Taussig Cancer Institute. He can be reached at Department of Solid Tumor Oncology, Cleveland Clinic, Mail Code R35, 9500 Euclid Ave., Cleveland, OH 44195. Disclosure: Shepard reports no relevant financial disclosures.

The approval process also involves many steps — such as protocol development and activation, patient accrual, data analysis and the like — that are not directly related to the FDA.

All of them could be streamlined to markedly improve efficiency.

There are two specific points to consider at the FDA level.

The first is the endpoint required for approval. The FDA has generally insisted on an OS endpoint for drug approval due to its objectivity. However, the chronicity of many cancers today and the numbers of confounding regimens makes it difficult to prove an OS advantage is related to a specific agent, and the time required for analysis is long.

For example, an ovarian cancer patient who is receiving her investigational agent second line may go on to receive five or more additional treatments over the course of disease. There are instances in which PFS has been demonstrated to be an appropriate surrogate endpoint. Furthermore, a nontoxic intervention that prolongs PFS in a meaningful way may be worthy in its own right without requiring a survival advantage.

The second point involves the necessity of developing a dedicated companion diagnostic for our newer targeted agents. This can be complex and may lengthen the drug development timeline.

The FDA just granted marketing authorization for the first next-generation genomic sequencer (Collins FS. N Engl J Med. 2013;doi:10.1056/NEJMp1314561). This will hopefully allow the consideration of using platform-derived data to serve as companion biomarkers for new agents as cohorts of patients are characterized, eliminating the development time for the analyte-specific tests.

Paul Sabbatini, MD, is deputy physician-in-chief for clinical research at Memorial Sloan-Kettering Cancer Center. He can be reached at Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021; email: sabbatip@mskcc.org. Disclosure: Sabbatini reports no relevant financial disclosures.