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Should terminally ill patients have access to phase I drugs?
World Report
Should terminally ill patients have access to phase I drugs? Some patient advocacy groups in the USA want to force the Food and Drug Administration to give terminally ill patients access to promising drugs after phase I safety testing. But critics say that to do so would endanger patients and slow drug approval. Nellie Bristol reports. A US federal court is weighing a lawsuit that seeks to force the US Food and Drug Administration (FDA) to grant terminally ill patients who have no other treatment options access to unapproved therapies after initial safety testing. The appeal was argued before the US Court of Appeals for the District of Columbia on March 1. A decision is not expected for several weeks. Advocates of the move say a decision in their favour would ensure terminally ill patients have access to potentially life sustaining treatments that are currently unavailable. But opponents, including FDA, say such a decision could expose vulnerable patients to unsafe substances and might slow the approval of drugs for the general population. The suit claims that FDA’s current process for granting emergency use of therapies outside the clinical trial setting gives the agency “sole judgment” in determining access to drugs in development. It argues that under the advice of a doctor, dying patients should be able to assess for themselves the risks and benefits of unapproved treatments. “Under FDA regulations, the vast majority of patients with lifethreatening illnesses do not have access to promising new medications during the years of clinical testing and review required by FDA”, said plaintiff’s attorney Richard Samp. “The drugs remain unavailable even though there is evidence that they are safe and effective and even though patients have no alternative to the drugs other than to wait for their own deaths.” The FDA would not comment on the suit. Samp said any decision is likely to be appealed, perhaps as far as the Supreme Court. The Washington Legal Foundation is bringing the suit for patient advocates seeking to change the process used by the FDA to www.thelancet.com Vol 369 March 10, 2007
approve pre-market drug access for the terminally ill. The groups, led largely by relatives of patients who died without receiving treatments they were seeking, say that the process is cumbersome and confusing and is resulting in needless premature deaths. All parties, including FDA, agree that the system needs to be improved. But the question of how is raising issues ranging from the rights of the individual versus those of society to the ethics of clinical trials. Frank Burroughs, President of the Abigail Alliance for Better Access to Developmental Drugs, said that the lawsuit was born of frustration. Burroughs’ 21-year-old daughter Abigail was unable to gain access to an unapproved drug before she died of head and neck cancer in 2001. Burroughs said that his group met with FDA a number of times over the last 5 years in attempts to improve access to developmental drugs. The group’s first choice to fix the system is outlined in legislation introduced in Congress in 2005. The bill would provide expedited approval for treatments for life threatening disease and prohibit placebo only controls
for terminal conditions. Only patients who had exhausted all other treatment options, including those in clinical trials, would be eligible under the plan. The process outlined in the legislation was presented to FDA via a citizen’s petition, Burroughs said, but not implemented. Abigail Alliance participants say the bill, supported principally by Republicans and free market advocates, has little chance in the new Democrat-controlled Congress, which is focused on issues of drug safety. In response to criticism, the FDA proposed regulations in December, 2006, to expand and simplify its “treatment investigational new drug (IND)” process. The proposal is the agency’s third attempt in as many decades to address drug access issues for the seriously ill. The FDA says that although it has approved INDs for about 100 000 patients over the years, it acknowledges criticism that its system is unclear and inconsistent and could hinder access to drugs by those receiving care outside academic medical centres. Through the proposed rules, FDA says, it hopes to “increase awareness
The appeal was argued before the US Court of Appeals for the District of Columbia
815
World Report
Science Photo Library
The printed journal includes an image merely for illustration
and knowledge of expanded access programs and the procedures for obtaining investigational drugs”, thus making the treatments more widely available. Expanded access advocates say that instead of instituting needed reforms, the proposal simply reinforces the current dysfunctional system. Steven Walker, chief adviser for the Abigail Alliance, said that the regulations make permanent a system that is enormously time consuming both for doctors seeking access to treatments for patients and for drug companies interested in making therapies available. “It’s a system that simply doesn’t work“, he said. Walker accused the agency of being “focused on its own status quo” instead of listening and responding to concerns of patients and their families. But the regulations are supported by others, including the American Society of Clinical Oncology, the Association of American Medical Colleges, and the National Coalition for Cancer Survivorship (NCCS). The groups are part of an amicus brief filed on behalf of the FDA position in the lawsuit. NCCS president and chief executive officer Ellen Stovall said that the FDA process for facilitating individual access 816
to unapproved drugs has not been clearly defined, but that the proposed rules make it more transparent. “The guidance begins to clarify for the public what their opportunities are for obtaining drugs through treatment INDs and other means”, she said. She said that further steps, mainly educational efforts, are needed to ensure that the public knows about the process and how to work it. Stovall argues that allowing even dying patients “unfettered access” to any therapy available is not the answer. Adding that the NCCS remains unconvinced that such access is an appropriate substitute for what they believe “is good policy for the public at large”. Allowing access to treatments outside the clinical trial setting slows the general availability of some drugs by as much as a year by reducing the number of people in trials, Stovall said. When possible, people would choose the route that ensures they will receive the therapy being tested instead of risking the chance they will be assigned to the placebo arm of a trial. Stovall also is concerned that expanded access would result in end-oflife medical decisions based primarily on emotion. “There is very little discussion at that point on the part of families, patients, and physicians about what dying would look like. That rarely happens because we’re so geared toward trying anything that could work.…This is a society that doesn’t die well”, she commented. Stovall’s concerns are echoed by Dean Gesme, a medical oncologist and leader with the American Society of Clinical Oncology. He says that doctors should wait until a drug’s benefits and safety are proven before they recommend them to patients. He also points to the emotional state of dying patients and their families and says it’s medically irresponsible for doctors to facilitate patient’s frantic efforts “to take anything that they have some figment of their imagination suggesting might help”. That approach is particularly risky in the USA where companies and
researchers are desperate to get positive public relations for their products, Gesme said. “We live in a society and an economy that in order to get drugs developed it’s important for companies to promote them early.” In that environment, he said, researchers “kind of slip into the role of subtly prompting something when the science has not yet caught up to the hype. In that situation there’s always the risk that the hype will exceed the reality.” But MD Anderson Cancer Centre researcher Emil Freireich disagrees with that argument. He says that drugs that have gone through initial safety tests should be made available. “Once it enters phase II it should be available to anyone if the patient and the physician are willing to take the risk because of the potential benefit”, Freireich said. He said that the current system allows bureaucrats to be the final arbiters of what is essentially a medical decision. He further criticised the drug approval process as over-regulatory and the clinical trial system as an overly restrictive, self-perpetuating industry. “The IND [investigational new drug] process benefits no one”, he argued. “It doesn’t protect anyone who’s healthy because no one would give new drugs that are not indicated to people who are healthy. It doesn’t protect the dying patients who desperately want to participate in these trials.” Those with a long view on the subject note that FDA walks a fine line between ensuring drug safety and approving effective therapies in a timely manner. The agency comes under fire both for moving too slowly in approving drugs and for allowing access to potentially dangerous substances. Former FDA Commissioner Frank Young remarked recently that people are pushing for drugs that ultimately may not be proven to be safe and effective. “And then if something goes wrong, the same voice says, ‘FDA, where were you?’“, he said.
Nellie Bristol www.thelancet.com Vol 369 March 10, 2007
Should terminally ill patients have access to phase I drugs? Some patient advocacy groups in the USA want to force the Food and Drug Administration to give terminally ill patients access to promising drugs after phase I safety testing. But critics say that to do so would endanger patients and slow drug approval. Nellie Bristol reports. A US federal court is weighing a lawsuit that seeks to force the US Food and Drug Administration (FDA) to grant terminally ill patients who have no other treatment options access to unapproved therapies after initial safety testing. The appeal was argued before the US Court of Appeals for the District of Columbia on March 1. A decision is not expected for several weeks. Advocates of the move say a decision in their favour would ensure terminally ill patients have access to potentially life sustaining treatments that are currently unavailable. But opponents, including FDA, say such a decision could expose vulnerable patients to unsafe substances and might slow the approval of drugs for the general population. The suit claims that FDA’s current process for granting emergency use of therapies outside the clinical trial setting gives the agency “sole judgment” in determining access to drugs in development. It argues that under the advice of a doctor, dying patients should be able to assess for themselves the risks and benefits of unapproved treatments. “Under FDA regulations, the vast majority of patients with lifethreatening illnesses do not have access to promising new medications during the years of clinical testing and review required by FDA”, said plaintiff’s attorney Richard Samp. “The drugs remain unavailable even though there is evidence that they are safe and effective and even though patients have no alternative to the drugs other than to wait for their own deaths.” The FDA would not comment on the suit. Samp said any decision is likely to be appealed, perhaps as far as the Supreme Court. The Washington Legal Foundation is bringing the suit for patient advocates seeking to change the process used by the FDA to www.thelancet.com Vol 369 March 10, 2007
approve pre-market drug access for the terminally ill. The groups, led largely by relatives of patients who died without receiving treatments they were seeking, say that the process is cumbersome and confusing and is resulting in needless premature deaths. All parties, including FDA, agree that the system needs to be improved. But the question of how is raising issues ranging from the rights of the individual versus those of society to the ethics of clinical trials. Frank Burroughs, President of the Abigail Alliance for Better Access to Developmental Drugs, said that the lawsuit was born of frustration. Burroughs’ 21-year-old daughter Abigail was unable to gain access to an unapproved drug before she died of head and neck cancer in 2001. Burroughs said that his group met with FDA a number of times over the last 5 years in attempts to improve access to developmental drugs. The group’s first choice to fix the system is outlined in legislation introduced in Congress in 2005. The bill would provide expedited approval for treatments for life threatening disease and prohibit placebo only controls
for terminal conditions. Only patients who had exhausted all other treatment options, including those in clinical trials, would be eligible under the plan. The process outlined in the legislation was presented to FDA via a citizen’s petition, Burroughs said, but not implemented. Abigail Alliance participants say the bill, supported principally by Republicans and free market advocates, has little chance in the new Democrat-controlled Congress, which is focused on issues of drug safety. In response to criticism, the FDA proposed regulations in December, 2006, to expand and simplify its “treatment investigational new drug (IND)” process. The proposal is the agency’s third attempt in as many decades to address drug access issues for the seriously ill. The FDA says that although it has approved INDs for about 100 000 patients over the years, it acknowledges criticism that its system is unclear and inconsistent and could hinder access to drugs by those receiving care outside academic medical centres. Through the proposed rules, FDA says, it hopes to “increase awareness
The appeal was argued before the US Court of Appeals for the District of Columbia
815
World Report
Science Photo Library
The printed journal includes an image merely for illustration
and knowledge of expanded access programs and the procedures for obtaining investigational drugs”, thus making the treatments more widely available. Expanded access advocates say that instead of instituting needed reforms, the proposal simply reinforces the current dysfunctional system. Steven Walker, chief adviser for the Abigail Alliance, said that the regulations make permanent a system that is enormously time consuming both for doctors seeking access to treatments for patients and for drug companies interested in making therapies available. “It’s a system that simply doesn’t work“, he said. Walker accused the agency of being “focused on its own status quo” instead of listening and responding to concerns of patients and their families. But the regulations are supported by others, including the American Society of Clinical Oncology, the Association of American Medical Colleges, and the National Coalition for Cancer Survivorship (NCCS). The groups are part of an amicus brief filed on behalf of the FDA position in the lawsuit. NCCS president and chief executive officer Ellen Stovall said that the FDA process for facilitating individual access 816
to unapproved drugs has not been clearly defined, but that the proposed rules make it more transparent. “The guidance begins to clarify for the public what their opportunities are for obtaining drugs through treatment INDs and other means”, she said. She said that further steps, mainly educational efforts, are needed to ensure that the public knows about the process and how to work it. Stovall argues that allowing even dying patients “unfettered access” to any therapy available is not the answer. Adding that the NCCS remains unconvinced that such access is an appropriate substitute for what they believe “is good policy for the public at large”. Allowing access to treatments outside the clinical trial setting slows the general availability of some drugs by as much as a year by reducing the number of people in trials, Stovall said. When possible, people would choose the route that ensures they will receive the therapy being tested instead of risking the chance they will be assigned to the placebo arm of a trial. Stovall also is concerned that expanded access would result in end-oflife medical decisions based primarily on emotion. “There is very little discussion at that point on the part of families, patients, and physicians about what dying would look like. That rarely happens because we’re so geared toward trying anything that could work.…This is a society that doesn’t die well”, she commented. Stovall’s concerns are echoed by Dean Gesme, a medical oncologist and leader with the American Society of Clinical Oncology. He says that doctors should wait until a drug’s benefits and safety are proven before they recommend them to patients. He also points to the emotional state of dying patients and their families and says it’s medically irresponsible for doctors to facilitate patient’s frantic efforts “to take anything that they have some figment of their imagination suggesting might help”. That approach is particularly risky in the USA where companies and
researchers are desperate to get positive public relations for their products, Gesme said. “We live in a society and an economy that in order to get drugs developed it’s important for companies to promote them early.” In that environment, he said, researchers “kind of slip into the role of subtly prompting something when the science has not yet caught up to the hype. In that situation there’s always the risk that the hype will exceed the reality.” But MD Anderson Cancer Centre researcher Emil Freireich disagrees with that argument. He says that drugs that have gone through initial safety tests should be made available. “Once it enters phase II it should be available to anyone if the patient and the physician are willing to take the risk because of the potential benefit”, Freireich said. He said that the current system allows bureaucrats to be the final arbiters of what is essentially a medical decision. He further criticised the drug approval process as over-regulatory and the clinical trial system as an overly restrictive, self-perpetuating industry. “The IND [investigational new drug] process benefits no one”, he argued. “It doesn’t protect anyone who’s healthy because no one would give new drugs that are not indicated to people who are healthy. It doesn’t protect the dying patients who desperately want to participate in these trials.” Those with a long view on the subject note that FDA walks a fine line between ensuring drug safety and approving effective therapies in a timely manner. The agency comes under fire both for moving too slowly in approving drugs and for allowing access to potentially dangerous substances. Former FDA Commissioner Frank Young remarked recently that people are pushing for drugs that ultimately may not be proven to be safe and effective. “And then if something goes wrong, the same voice says, ‘FDA, where were you?’“, he said.
Nellie Bristol www.thelancet.com Vol 369 March 10, 2007