BILL ANALYSIS Ó
AB 159
Page A
Date of Hearing: April 7, 2015
ASSEMBLY COMMITTEE ON HEALTH
Bonta, Chair
AB
159 (Calderon) - As Introduced January 21, 2015
SUBJECT: Investigational drugs, biological products, and
devices
SUMMARY: Permits a manufacturer of a drug, biological product,
or device (experimental drug or device) that has not yet
received federal or state approval to market to make the product
available to eligible patients with terminal illnesses, as
specified. Specifically, this bill:
1)Allows, but does not require, the manufacturer of an
experimental drug or device to provide an investigational drug
or device to an eligible patient, as defined. Specifies that
the manufacturer may provide for free, or may charge the
patient to pay for the costs of the drug or device.
2)Defines an eligible patient as one who has met all the
following criteria:
a) Has a terminal illness, defined as a disease that,
without life-sustaining procedures, will result in death in
the near future or a state of permanent unconsciousness
from which recovery is unlikely;
AB 159
Page B
b) Has considered all other treatment options currently
approved by the U.S. Food and Drug Administration (FDA);
c) Has been unable to participate in a clinical trial
within 100 miles of their home, or has not been accepted,
as specified;
d) Has received recommendation from their physician for the
drug or device;
e) Has given written, informed consent, as specified; and,
f) Has documentation form their physician attesting that
the patient has met these requirements.
3)Allows, but does not require, a health plan to provide
coverage for the drug or device, or the costs of services
related to the use of the drug or device.
4)Prohibits a state regulatory board form revoking, failing to
renew, or taking any other disciplinary action against a
physician's license based on the recommendation, prescription,
or treatment of the drug or device, provided the
recommendation or prescription is consistent with the medical
standards of care.
AB 159
Page C
5)Prohibits a state agency from altering a recommendation made
to the federal Centers for Medicare and Medicaid Services
regarding a health care provider's certification to
participate in the Medicare or Medicaid program based solely
on the recommendation from an individual health care provider
that a patient have access to the drug or device.
6)Prohibits an official, employee, or agent of the state from
blocking or attempting to block an eligible patient's access
to an investigational drug or device pursuant to this article.
Specifies that counseling, advice, or a recommendation
consistent with medical standards of care from a licensed
healthcare provider is not a violation of this section.
7)Specifies that this article does not create a private cause of
action against a manufacturer of an investigational drug or
device, or against any other person or entity involved in the
care of an eligible patient using the drug or device, for any
harm done to the patient resulting from the drug or device, so
long as the manufacturer or other person or entity is
complying in good faith with the terms of this article, unless
there was a failure to exercise reasonable care.
EXISTING STATE
LAW:1)
1)Establishes the Sherman Food, Drug, and Cosmetic Law, which
regulates the packaging, labeling, and advertising of drugs
and devices, administered by the Department of Public Health
(DPH).
2)Prohibits, in the Sherman Law, the sale, delivery, or giving
AB 159
Page D
away of a new drug or device unless it is either
a) A new drug or new device for which DPH has approved a
new drug or device application, and has not withdrawn,
terminated, or suspended that approval; or,
b) A new drug, and a new drug application has been approved
for it by the FDA, pursuant to federal law, or it is a new
device for which a premarket approval application has been
approved, and that approval has not been withdrawn,
terminated, or suspended under the FDA.
3)Establishes the Protection of Human Subjects in Medical
Experimentation Act which prescribes various protections for
subjects of medical experimentation relating to a bill of
rights; informed consent procedures and documentation; and,
the provision of specified disclosures, including the right
for a subject to give or withdraw consent freely and without
duress. Imposes penalties for violations of these
protections.
4)Requires health plans and insurers to provide an external,
independent review process to examine plan's coverage denials
of experimental or investigational therapies for individual
enrollees who have a life-threatening or seriously
debilitating condition and who meet other specified criteria.
5)Requires health plans and insurers to provide coverage for all
routine patient care costs relative to the treatment of an
enrollee or insured diagnosed with cancer and accepted in an
FDA-approved cancer clinical trial, Phase I-IV, if the
enrollee's treating physician, recommends participation in the
clinical trial after determining such participation has a
meaningful potential to benefit the enrollee or insured.
EXISTING FEDERAL LAW:
AB 159
Page E
1)Establishes the federal Food, Drug, and Cosmetic Act, which
grants authority to the FDA to oversee the safety of food,
drugs, and cosmetics.
2)Prohibits any new drug from being introduced into interstate
commerce unless an application has been approved by the FDA.
3)Under federal regulation:
a) Requires clinical trial sponsors to submit an
Investigational New Drug (IND) application to the FDA for
clinical investigation of a new drug or new indication of
an approved drug, with certain exceptions;
b) Requires review and approval from an Institutional
Review Board (IRB) before a clinical study can be initiated
under an IND;
c) Defines an IRB as an appropriately constituted group
that has been designated to review and monitor biomedical
research involving human subjects, to ensure that a
clinical trial is ethical and that the rights of study
participants are protected; and,
d) Authorizes an IRB to approve, require modifications in,
or disapprove research, or to suspend or terminate approval
of research that is not being conducted in accordance with
AB 159
Page F
the IRB's requirements or that has been associated with
unexpected serious harm to subjects.
4)Establishes the Office for Human Research Protections (OHRP),
which provides leadership in the protection of the rights,
welfare, and wellbeing of subjects involved in research
conducted or supported by the U.S. Department of Health and
Human Services (HHS). OHRP helps ensure this by providing
clarification and guidance, developing educational programs
and materials, maintaining regulatory oversight, and providing
advice on ethical and regulatory issues in biomedical and
social-behavioral research.
FISCAL EFFECT: This bill has not yet been analyzed by a fiscal
committee.
COMMENTS:
1)PURPOSE OF THIS BILL. According to the author, this bill
removes barriers to accessing potentially life-saving drugs
for terminally-ill patients and doctors who believe an
investigational drug or device could be their last hope for
survival. The author further states that those patients that
have exhausted all other treatment options, and are not
eligible for clinical trials, often seek access to INDs, but
face a variety of hurdles. These patients may seek
compassionate use exemptions from the FDA, but the process is
cumbersome and approval comes too late for many. This bill
removes barriers for patients who need to immediately obtain
investigational treatments, while also protecting physicians,
hospitals, and manufacturers from retribution.
2)BACKGROUND. Patient requests for access to drugs and
biologics prior to their approval have long created a dilemma
for regulators, who must balance the needs of patients and
their families who believe that an experimental product could
AB 159
Page G
save their life, with ensuring the safety of the greater
population through tightly controlled clinical trials and drug
approval. This issue has become increasingly visible and
difficult in recent times, as views about the inherent right
of patients in certain situations to unapproved products have
been expressed by patients and their advocates, state
legislators, members of Congress, and some court cases. In
2014 four states adopted legislation similar to this bill
(Colorado, Louisiana, Michigan, and Missouri) and one state
(Arizona) adopted a resolution to place the issue on the
November 2014 ballot, where it was approved by voters. To
date, at least 20 states are considering similar legislation
in 2015.
3)FDA AND STATE APPROVAL OF DRUGS. FDA has jurisdiction over
all drugs that are sold across state lines. State law gives
DPH the authority to approve for market a drug or device that
is sold in California. If a product has received FDA
approval, then DPH automatically recognizes the product's
approval. In rare instances when a drug or device will be
sold only in the state of California, and will not be
distributed through interstate commerce, then California would
be the approving body. According to DPH, this has resulted in
a few instances where California has approved a new drug or
device application.
Independent from drug or device applications, manufacturers of
drugs and devices must be licensed to manufacture in the state
of California. FDA does not approve manufacturers, but they
do conduct inspections to ensure manufacturers are in
compliance with good manufacturing practices. Under
California Law, drug manufacturers must be licensed with DPH
even if not registered with FDA.
AB 159
Page H
4)THE CLINICAL TRIAL PROCESS. A clinical trial is a study that
is carefully designed to test the benefits and risks of a
specific medical treatment or intervention, such as a new
drug. The FDA requires a multi-phase clinical trials process
to be completed before deciding if an investigational medicine
is safe and effective for a broader patient population.
a) Phase I is a clinical trial using a small group of
healthy individuals (generally 20 to 80 volunteers). This
stage is designed to assess the toxicity and dosing of a
drug and whether or not there are harmful side effects
associated with the drug. Phase I trial does not establish
either the safety or efficacy of a drug. According to the
FDA, the goal in this phase is to determine what the drug's
most frequent side effects are in healthy volunteers, how
the drug is metabolized and excreted, and whether there is
an unacceptable level of toxicity associated with taking
the drug.
b) Phase II clinical trials involve control groups and
experimental groups (up to 300 individuals total) to
determine whether the drug is effective for the intended
purpose on a particular disease or condition. This phase
aims to obtain preliminary data on whether the drug works
in people who have a certain disease or condition.
c) Phase III begins if the drug proves to be effective in
Phase II. These studies gather further information on the
drug's safety and effectiveness on different populations
(several hundred to about 3,000 participants) and tests
varying levels of doses in combination or in comparison
with different drugs.
d) Phase IV studies are post-marketing studies the sponsor
AB 159
Page I
has agreed to do after the FDA approves a drug. These
studies gather additional information on a product's
safety, efficacy, and optimal use.
5)Expanded Access to investigational products through the FDA.
If a patient is unable to enroll in a clinical trial, the FDA
expanded access exemption, also called "compassionate use,"
provides a pathway for patients to gain access to
investigational drugs or devices for serious diseases or
conditions. A licensed physician is able to apply for
expanded access under a single patient IND Application on
behalf of the patient. The supervising physician must be
willing to commit to oversee the treatment, work with the
manufacturing company and FDA, obtain the drugs, monitor the
patient during the course of treatment, and file necessary
paperwork. The FDA states that they receive approximately
1,000 expanded use applications per year, and has approved
more than 99% of those applications. In the last four years,
the FDA has denied only 33 of nearly 6,000 expanded access
requests.
a) FDA directives allow physicians to request expanded
access for patients in an emergency situation over the
phone or by "other rapid means of communication." The FDA
states that authorization of the emergency use may be given
by an FDA official over the telephone, provided the
physician explains how the expanded access use will meet
federal requirements for expanded access use and agrees to
submit an expanded access submission within 15 working days
of FDA"s initial authorization of the expanded access use.
b)
Critics of the FDA process have raised concerns that the
Expanded Use application is too cumbersome for physicians
and patients to complete. Critics claim that it currently
requires an application that takes doctors 100 hours to
AB 159
Page J
fill out. The response time from the FDA ranges from a few
days to a few months. On February 4, 2015, the FDA
announced that it would be streamlining the expanded use
application process, and stated that the proposed
application will allow physicians to apply for experimental
drugs in just 45 minutes. The FDA draft guidance on the
new application process is currently in the 60-day public
comment period.
6)Distinction from off-label prescribing. The FDA does not
regulate the practice of medicine. After the FDA has approved
a drug, a doctor is free to decide how to use it. A provider
has the ability, under his/her medical license, to use an
FDA-approved and legally-marketed drug or device to treat a
patient, even if that treatment is outside of the product's
FDA labeling, also known as "off-label" prescription. There
are times, however, when a provider may think that the best
possible treatment for a patient is a drug or medical device
that is not yet FDA-approved or legally marketed in the United
States. In such cases, a provider cannot write a prescription
for or order the treatment through usual mechanisms, and the
physician may seek to gain access for the patient through an
existing clinical trial or using compassionate use exemptions.
Compassionate use might also be sought for drugs and devices
that are approved in other countries, but not within the
United States.
7)COURT HISTORY. In 2005,the Abigail Alliance for Better Access
to Developmental Drugs, with the mission of facilitating
access to experimental drugs for patients, sued the FDA,
claiming a constitutional due process right for terminally ill
patients to access unapproved drugs. A US District court
disagreed and the case was heard by the US Court of Appeals
for the District of Columbia Circuit. In 2006, a divided
three-judge panel of the D.C. Circuit agreed with the
Alliance, finding that where there are no other FDA-approved
treatment options, a terminally ill patient has a
constitutionally-protected "fundamental right" to access
investigational drugs. In 2007, the D.C. Circuit reheard the
AB 159
Page K
case "en banc" and reversed the panel decision. The Alliance
then filed a petition asking the U.S. Supreme Court to hear
the case but the Supreme Court denied the petition, so for now
the Court of Appeals decision stands.
8)ENSURING PATIENT SAFEGUARDS THROUGH THE INSTITUTIONAL REVIEW
BOARD PROCESS. Federal law requires that any FDA expanded use
requests for any investigational drug be reviewed by an IRB,
or ethics committee; a group of medical experts that evaluates
the risks of an experimental treatment and ensures the patient
understands them as well. The IRB process protects the people
receiving the drug and ensures that the risks are reasonable
given the potential benefits. A physician submits the
proposed experimental protocol, including duration of
treatment and the informed consent documents to an IRB, which
reviews them to make sure patients are fully aware of
potential risks and are willing to accept the level of
potential risk associated with the drug. IRBs are usually
associated with a hospital or research institution, but there
are independent IRBs available for physicians not associated
with such an institution. The OHRP requires and regulates the
use of IRBs for any research supported or conducted by HHS
(which includes National Institutes on Health funded
research). While OHRP oversees IRB processes in general, each
institution has their own review board, timelines, and
specific policies. Physicians are governed primarily by the
IRB committee policies set up by their specific institution.
9)CONTROVERSY OVER RESEARCH WITHOUT IRB APPROVAL. In 2012, two
neurosurgeons from the University of California, Davis (UC
Davis) were accused of performing an unapproved experimental
procedure on three dying brain cancer patients. In these
cases, the neurosurgeons obtained informed consent from the
patients but did not communicate to the patients that the
procedure had not been approved by the FDA as an
AB 159
Page L
investigational new treatment for testing in human subjects.
The patients were also not informed that the research was not
approved by UC Davis' IRB. Two of the patients developed
sepsis and died within weeks of their surgeries. Both
surgeons involved were banned from performing surgery and
later resigned from the University. In response to these
incidences, UC Davis has since tightened its innovated use
policy to expressly prohibit any use of a non-FDA approved
drug, biologic, or device without formal IRB and, as required,
FDA approval, regardless of the purpose of the use.
10)Who will pay? If a patient is enrolled in an FDA-approved
clinical trial for cancer, California law requires that the
insurer pay for routine patient care costs. Health plans do
not have to pay for experimental drug, but in most cases these
drugs are given to clinical trial participants at no cost by
the government agency, university medical center or
pharmaceutical company that sponsors the trial.
a) This bill authorizes, but does not require any health
plan, insurer, or manufacturer to pay for the cost of the
medication. Typically, health plans limit coverage to only
FDA approved drugs and devices. In addition, when a plan
reviews potential drugs for their formulary, they review
data on clinical effectiveness, cost of the drug, potential
side effects or harm, and the costs associated with
treating that. Under current law, a patient denied
coverage for an experimental drug or device may appeal the
decision and request evaluation by Independent Medical
Review, although this can be a time-consuming process.
Taken together, it is unlikely that health plans would
cover the cost of experimental drugs obtained through this
legislation.
AB 159
Page M
b) In the expanded access use protocols the FDA allows,
after their review and approval, the manufacturer to charge
a nominal fee for the cost of providing the experimental
drug or device. This bill authorizes a manufacturer to
charge for the experimental drug or device, without any
review or approval.
11)SUPPORT. Supporters argue that patients with no other
treatment options should be able to take on more risk than
healthy patients would otherwise choose. The Los Angeles
County Board of Supervisors supports this bill, stating that
terminally ill patients, who have exhausted their options to
find a cure and who have identified a physician and
pharmaceutical company willing to assist them, deserve the
right to experimental treatments that could prolong their
lives.
12)OPPOSITION. The Association of Northern California
Oncologists opposes this bill citing several reasons,
including the difficulty identifying "terminally-ill"
patients, the lack of an informed consent process to protect
patients seeking these drugs, and the lack of appropriate
physician supervision of the use of these drugs. The
California Medical Association states opposition due to
significant patient safety concerns with allowing access to
unproven drugs outside the FDA's clinical trials and
compassionate use programs. The FDA ensures efficacy and
safety of using such drugs, and once they are removed from
these processes there is no longer an ability to protect
patients and provide proper oversight. Additionally, this
bill may be both premature and unnecessary, and could also
potentially detract from the FDA rulemaking process that is
currently ongoing. The California Nurses Association (CNA)
states that this bill erroneously suggests that consumers do
AB 159
Page N
not have access to these drugs because physicians fear their
liability to practice medicine would be compromised and their
liability increased if they were to recommend such treatment.
CNA points out that "nothing in this legislation impacts the
availability of drugs to terminally ill patients unless the
manufacturers of the drugs allow it to be used in advance of
FDA approval".
13)STATEMENT OF CONCERN. The Pharmaceutical Research and
Manufacturers Association (PhRMA) filed a letter of concern
with this Committee, stating that Right-to-Try legislation,
while well-intentioned, could have serious unintended
consequences that must be taken into consideration. Robust
clinical trials are one of the key elements in bringing new
therapies to market. PhRMA states that it is imperative that
investigational drugs be used within the boundaries of
carefully constructed and monitored clinical trials to ensure
patient safety, and to glean key understandings about the
safety, efficacy, and uses of investigational drugs.
Furthermore, PhRMA is concerned with the lack of oversight and
accountability in this legislation. Both clinical trials and
the FDA's expanded access program requires that patients be
given these under the close supervisions of a physician and
other health care providers to closely monitor patient
reactions. Allowing blanket access to these drugs outside of
monitored trials could yield catastrophic results for the
patient.
14)RELATED LEGISLATION:
a) SB 128 (Wolk) permits a competent, qualified individual
who is a terminally ill adult to receive a prescription for
aid in dying medication if certain conditions are met.
This bill was approved by the Senate Health Committee on
March 17, 2015 and is currently pending in the Senate
AB 159
Page O
Judiciary Committee.
b) SB 149 (Stone) is largely similar to this bill, with
differences primarily in definitions and liability
exemptions. SB 149 is pending in Senate Health committee on
April 15, 2015.
c) SB 715 (Anderson) is largely the same as this bill with
some differences in definitions. SB 715 is pending in
Senate Health committee on April 15, 2015.
15)POLICY COMMENTS.
a) Is this bill premature? In response to requests from
advocates, and the passage of several right-to-try bills in
states, the FDA is promulgating new regulations to
dramatically shorten the length of time it takes to apply
for expanded use access. The proposed regulations were
announced on February 4th, 2015 and are currently open for
public comment. Given that the FDA may arrive at the
intended purpose of this goal in the very near future, the
committee may wish to consider whether this bill is
premature.
b) Will this bill achieve its intended goal? Shipping an
investigational drug across state lines is illegal without
an approved IND from the FDA. If a manufacturer agreed to
provide their investigational drug to a patient under this
bill, they would be in violation of federal law. Drug
manufacturers are not exempted from FDA rules under this
law, and therefore companies interested in gaining full
regulatory approval for their products are unlikely to
ignore federal regulation.
AB 159
Page P
Similar bills in other states have been enacted too recently
to assess their impact. Anecdotal news reports suggest
that when approached by patients directly, manufacturers
are requesting that they go through the FDA process
instead.
c) How would we know is this policy is effective? The FDA
tracks and provides data on how many expanded use
exemptions they approved. Neither FDA nor any other
entity, however, keeps track of how many requests are
turned down by companies. Under this bill, the state would
not know how many requests are being made to companies.
The Committee may wish to consider whether it would be
appropriate to require physicians report to an appropriate
state agency the status of their request and use of the
experimental drug. That would help the author/Legislature
know if the policy is useful.
d) Is there adequate oversight? This bill does not specify
who, if anyone, is responsible for overseeing the patient's
progress after obtaining the drug or device. Under FDA's
expanded access regulations, the manufacturer or treating
physician submit a written summary of the results of the
expanded access use, including any adverse events. Under
this bill, it is not clear if the supervising physician or
the manufacturer would have to notify the FDA of patient
outcomes or adverse reactions. It is unclear if the
physician would even have to notify the manufacturer.
e) Conflict with other bills this session. There are two
other bills introduced this session that address this same
issue. Assuming all the bills continue to move forward
this year, subsequent amendments will be required.
AB 159
Page Q
16)SUGGESTED AMENDMENTS
a) Prognosis of terminal illness is a matter a clinical
judgment; it is a subjective probability determined by the
provider. Studies have shown that physicians are often not
able to provide an accurate prognosis,<1> and that accuracy
diminishes as the length of time prior to projected death
increases, a problem known as the horizon effect.
Specifically, the ability to discriminate between patients
who would survive for one year and those who would not has
been found to be very poor.<2> California statutes
currently have several different, often inconsistent,
definitions of terminal illness.
Additionally, the FDA does not specify terminal illness, and
instead has a definition that is more expansive than this
bill: "serious or immediately life-threatening disease or
condition". For example, a patient diagnosed with
Amyotrophic Lateral Sclerosis may have more than 5 years
life expectancy from the date of diagnosis, but with
serious impacts on day-to-day functioning, and could
therefore apply for expanded access through the FDA but not
through this bill. The author should strike the definition
of terminal illness and instead use terminology consistent
with the FDA expanded use exemptions. This would remove
the need for a subjective definition of terminal illness,
and offer parity with federal regulations on this same
issue (CFR 21, Section 312.300).
"Immediately life-threatening disease or condition"
means a stage of disease in which there is reasonable
----------------------
<1> Glare, P., K. Virik, M. Jones, M. Hudson, S. Eychmuller, J.
Simes, and N. Christakis. "A systematic review of physicians'
survival predictions in terminally ill cancer patients." BMJ
327, no. 7408 (2003): 195.
<2> Mackillop, William J., and Carol F. Quirt. "Measuring the
accuracy of prognostic judgments in oncology." Journal of
clinical epidemiology 50, no. 1 (1997): 21-29.
AB 159
Page R
likelihood that death will occur within a matter of
months or in which premature death is likely without
early treatment. "Serious disease or condition" means
a disease or condition associated with morbidity that
has substantial impact on day-to-day functioning.
"Terminal illness" means a disease that, without
life-sustaining procedures, will result in death in
the near future or a state of permanent
unconsciousness from which recovery is unlikely.
b) Similar laws in other states are too recent assess
whether the laws are actually providing dying patients
greater access to experimental drugs compared with what the
FDA already permits. This bill does not require any agency
or company to track whether patients are able to acquire
the experimental drugs or devices they are seeking. The
author should consider requiring reporting to an
appropriate state agency the status or results of requests
made, the duration of treatments, or costs paid by patients
for the experimental drugs or devices.
c) Informed consent requirements for experimental
treatments are already codified in the "Protection of Human
Subjects in Medical Experimentation Act" (HSC 24170-24179).
To remain consistent with the high standard of informed
consent in current law, subdivision (g) should be amended
to include the appropriate reference:
(g)? and attested to by the patient's physician and a
witness. The written, informed consent shall be
consistent with Chapter 1.3, Division 20 of the Health
and Safety Code and, and do all of the following:
AB 159
Page S
d) Even when treating a single, terminally ill patient, the
use of an unapproved drug is still considered human
experimentation and should be bound by the highest
scientific ethical standards. Lack of IRB oversight in
this bill weakens patient protections. Most institutions
have IRB policies in place that physicians must follow.
Because this bill does not specify IRB review of treatment
protocol and informed consent, physicians not bound and
their institutional policies might not undergo this ethical
review. This bill should be amended to include reference
to IRB.
(g) "Written, informed consent" means a written
document that has been approved by the physician's
institutional review board or an accredited
independent institutional review board, is signed by
an eligible patient, or his or her legally authorized
representative where the patient lacks the capacity to
consent, and attested to by the patient's physician
and a witness.
REGISTERED SUPPORT / OPPOSITION:
Support
County of Los Angeles
Opposition
AB 159
Page T
Association of Northern California Oncologists
California Medical Association
California Nurses Association
Analysis Prepared
by: Dharia McGrew/HEALTH/(916) 319-2097