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