A new access program and registry developed by the American Society of Clinical Oncology to facilitate use of off-label cancer drugs could serve as a model for independent bodies that could manage early access to experimental therapies, even though ASCO itself is not tackling compassionate use.

ASCO's initiative is designed to match off-label targeted cancer therapies to individual patients likely to benefit based on the genomic profile of their tumors, while collecting data about new uses for approved drugs.

"We should develop programs to make it easier to access drugs, but require more detailed reporting of outcomes, which is just the opposite of the current situation," CMO Richard Schilsky told BioCentury. "Doing so would provide treatment options to patients in need and allow us to learn from all these patient experiences."

Like programs that grant early access to experimental medicine, or compassionate access, ASCO plans to limit its off-label initiative to patients who are not eligible for trials and who have no alternatives.

A central feature of the program is the establishment of an honest broker to make decisions about the allocation of targeted therapies and to collect and analyze outcomes data.

If the project is successful for off-label therapies, it could inspire similar schemes based on honest brokers affiliated with medical specialty societies that would serve as intermediaries between drug companies and patients seeking early access to experimental medicines.

PhRMA, BIO and their member companies, as well as patient organizations and congressional staff, are all engaged in separate discussions - primarily behind closed doors - about creating new policies to facilitate equitable early access to experimental therapies.

As BioCentury proposed in a March 31 Commentary, the creation of independent third parties is one of several options under consideration.

To be successful, early access policies will have to be aligned with several social and scientific trends: social media-fueled patient empowerment; the development of highly effective targeted therapies made possible by the integration of molecular diagnostics into drug development and clinical practice; and a "right to try" movement that is gaining traction among state and federal lawmakers.

Access and registry

According to Schilsky, ASCO's program was prompted by the realization that many oncologists lack the expertise required to make treatment decisions based on genomic test results, as well as the difficulty patients face in getting reimbursement for off-label prescriptions.

"I'm reacting to the rapid penetration of genetic profiling in the cancer patient population, with many comprehensive cancer centers, community hospitals, and commercial labs setting up to do multiplex testing," Schilsky said. Interpreting tests results to determine whether a specific genomic variant is clinically actionable is "challenging even for experts," he added.

Physicians would submit a genomic profile of a patient's tumor from a CLIA-certified lab, along with a proposed treatment plan and request for off-label use of a targeted therapy, to an honest broker. The dosing and regimen would be consistent with labeling for approved indications.

To facilitate such requests, ASCO is considering establishing an Internet-based "tumor board" of clinical oncologists and molecular pathologists that would review genomic test results and provide advice to physicians, including potential treatment options.

The honest broker would review the application. For approved applications, the honest broker would arrange for shipment of a three-month supply of the drug. The patient's response would be evaluated and, if appropriate, additional supplies would be dispensed.

Schilsky said he is "writing a clinical protocol for what will essentially be an observational study."

The protocol will be "for patients who have exhausted all treatment options, but who have reasonable performance status, so they have a meaningful chance of benefiting from therapy if benefit can be derived."

In addition to validating treatment plans, the honest broker would maintain a registry with information about patient characteristics and outcomes.

ASCO is speaking with several for- and not-for profit entities that could serve as the honest broker, Schilsky said.

He noted that clarity about the rules will be key to making an honest broker acceptable to patients and the public.

"Any time a third party makes a decision, that decision has to be made according to prespecified guidelines," he said. "It has to be transparent, and as objective as possible - and people have to understand going in there will be some cases that will be rejected."

Support needed

Drug companies will be asked to supply off-label drugs at no cost, and insurance companies will be asked to pay for all other treatment expenses, Schilsky said. In return, drug companies and payers would benefit from the generation of data about off-label uses.

Schilsky has approached six pharmaceutical companies to discuss the project. "All have expressed interest in the idea. None said they are definitely in," he said. "No one has said no."

Schilsky said he also has presented the concept to "a couple of insurance companies. The general response has been: 'We are OK paying for the healthcare costs as long as we don't have to pay for the expensive drugs.'"

Schilsky also has discussed the concept with senior FDA officials.

"FDA feels that if something like this was set up, it would enhance their understanding of how these drugs are being used. FDA may turn out to be a champion of this kind of approach," he said.

Schilsky said ASCO hasn't determined how much the project will cost or how much demand there will be.

"We plan to start this as a pilot project with a limited number of physician practices scattered around the country, with as many drugs as we can get into the program initially," he said. "We want to see if this is feasible, if we can we get the drugs to patients in a reasonable period of time, if there are any significant patient benefits from the approach, and if can we get the necessary data from doctors."

ASCO hopes to get the pilot running before year end.

Pivot point

In a paper describing the program in Nature Reviews Clinical Oncology this month, Schilsky mentioned the possibility of including investigational drugs. But he told BioCentury ASCO has decided to stick with approved drugs.

"It was a question of not biting off more than I could chew. Once you get into investigational drugs, you get into a higher level of complexity regarding human subject participation and regulatory oversight," he said.

"There are at least 25 marketed targeted anticancer treatments that hit 15 or so different genetic targets," Schilsky added. "We already have a good starting point of the universe of marketed drugs without having to get into investigational drugs."

ASCO's project is inspired in part by the growing sophistication of patients who read about targeted therapies on the Internet and request access to off-label therapies, Schilsky said.

Patient demand that is the result of social and news media reporting about new therapies is also propelling discussions among life sciences companies about policies for providing early access to experimental drugs.

"It feels like a pivot point" for early access, said Amrit Ray, CMO at Johnson & Johnson's Janssen Pharmaceuticals division. "It is positive to have great innovation for patients. It is positive to have empowerment of patients sharing information, with the ability to ask questions and be in touch."

J&J recently revised its policies on early access to investigational drugs, Ray said. The most visible result is a web page with clear information about accessing investigational drugs with contact information for physicians to request access (see Featured Links, A11).

"We stepped back and made sure the information on how to make a request was accessible in one place, with one phone number and one email address," Ray said. "We made sure those requests go to one common place and are quickly addressed by therapeutic area and disease experts."

He added that policies will need to adapt to the changing environment.

"When it comes to policies and frameworks for early access, we have to get in the mindset of continuously revisiting those approaches," said Ray. "Science is changing, patients are changing, and it makes great sense that approaches and frameworks for early access will evolve and change."

Ray said J&J is participating in discussions on early access policies at BIO and PhRMA, and he will participate in a closed meeting on early access at the Brookings Institution.

The April 29 workshop is being organized by Darshak Sanghavi, who is Merkin fellow and managing director of economic studies at Brookings' Engelberg Center for Health Care Reform.

Sanghavi told BioCentury the informal meeting is "primarily geared to identify common issues and experiences from major pharma companies, with the goal of identifying some themes that might be addressed in a formal, larger meeting to address compassionate use with a larger group if there is interest."

In addition to pharma company executives, the meeting will be attended by a bioethicist and a patient advocate.

Speaking on BioCentury This Week television, Sanghavi said there is a need to collect some basic information in order to craft new early access policies.

"If we don't even know the magnitude of the issue, then we really can't even decide how we're going to fix it," he said (see BioCentury This Week, April 13).

Nancy Goodman, founder and executive director of the advocacy organization Kids v Cancer, added that better policies probably would lead to more widespread access to investigational drugs.

"I suspect, frankly, that there are fewer compassionate uses issued than we as a society might want," she said.

Goodman endorsed the creation of organizations that are independent of drug manufacturers to review applications for early access. Such decisions could be made by a "third party that would be responsible for reviewing every case on an expedited basis, understanding both the challenges and limitations the company faces, and the probability of a particular investigational drug assisting a patient," she said.

Sanghavi suggested third party decision makers could absorb some of the administrative tasks and costs that are barriers for small companies to offer early access.

"It seems to me that the biggest cost is really the evaluation, the paperwork, maybe tracking [outcomes and] not really the manufacture of the drug, at least with limited exceptions," he said. "All of us can agree that the last thing we want to do is to impose additional regulatory burden and cost on people who are trying to make life-saving medications."

Right to try

Publicity about recent efforts by patients to obtain access to unapproved drugs, including the successful social media campaign launched by Josh Hardy's family, may have revived the fortunes of the "right to try" movement.

Last week, the Arizona Senate passed HCR 2005, a bill that would allow physicians to prescribe investigational products to eligible terminally ill patients who have no "comparable or satisfactory" FDA-approved treatment options.

The bill will be placed on the ballot for voter approval in November unless Gov. Janice Brewer vetoes it.

If the initiative passes, it would be possible for patients to receive access to experimental drugs with the consent of their physician and the drug manufacturer. FDA would have no oversight role, according to Christina Corieri, healthcare policy analyst at the Goldwater Institute, a libertarian think tank that drafted the legislation.

Just as the federal government has opted to exercise enforcement discretion in the face of state marijuana laws, it could choose to allow Arizona, and any other state that enacts a similar law, to make experimental drugs available to terminally ill patients without FDA oversight, Corieri said.

If FDA asserts federal preemption to prevent implementation of the law, the Goldwater Institute is prepared to litigate the case, she said.

"We believe the right to save your own life is a fundamental right protected by the Constitution," said Corieri.

According to Corieri, a 2006 ruling against the right to access experimental drugs, issued by the U.S. Court of Appeals for the District of Columbia Circuit, "is not binding on any other circuit" and does not apply in Arizona.

The case was filed by the Washington Legal Foundation (WLF) and Abigail Alliance for Better Access to Developmental Drugs (see BioCentury, Jan. 21, 2008).

Bills similar to HCR 2005 are pending in Louisiana and Missouri.

More sweeping legislation has been introduced in the U.S. Congress. The Compassionate Freedom of Choice Act (H.R. 4475), sponsored by Rep. Morgan Griffith (R-Va.), would allow manufacture, importation, distribution and sale of investigational products outside of a clinical trial for terminally ill patients without restriction by or reporting to FDA.

H.R. 4475 provides liability protection for investigational drug manufacturers; Arizona HCR 2005 does not include liability protection.

Political support for right to try legislation could accelerate efforts to craft new early access policies at BIO and PhRMA, which oppose efforts to bypass FDA regulation of experimental drugs.


Abigail Alliance for Better Access to Developmental Drugs, Lorton, Va.

American Society of Clinical Oncology (ASCO), Washington, D.C.

Biotechnology Industry Organization (BIO), Washington, D.C.

Brookings Institution, Washington, D.C.

Goldwater Institute, Phoenix, Ariz.

Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J.

Kids v Cancer, Washington, D.C.

Pharmaceutical Research and Manufacturers of America (PhRMA), Washington, D.C.

Washington Legal Foundation (WLF), Washington, D.C.