Compassionate Use

HIGH SCHOOL BIOETHICS PROJECT COMPASSIONATE USE

OVERVIEW PROCEDURES AND ACTIVITIES

This module encourages students to think This unit uses a student-centered and interactive through ethical and social issues surrounding the approach to teaching. Activities are designed to compassionate use of experimental drugs and de- allow for a maximum degree of student partici- vices. Students will be exposed to the process of pation and collaboration. Each activity is marked testing and licensing new drugs with the US Food as an individual-, partner-, or group activity, or as and Drug Administration in an effort to understand a teacher-directed class discussion. the motivations for compassionate use and the ethical issues it raises. The module relies on a The following icons are used to designate the case-based approach to learning. Three cases are different types of activities: presented, and students will be led in an analysis of the issues presented in the cases.

Individual Activity CONTENTS Partner Activity 1. Introduction to Topic 2. Definitions Group Activity 3. Case Study: The Effects of Social Media 4. Case Study: When the Drug Fails 5. Case Study: Unequal Access 6. Conclusion Teacher-Directed Class Discussion 7. References and Additional Resources

LEARNING OUTCOMES

1. Learn the basics of compassionate use 2. Understand the motivations and ethical dilem- mas behind the development of compassionate use 3. Examine case studies and formulate opinions about the current state of compassionate use 4. Brainstorm possible solutions for the future of compassionate use

DC 1/27/2020 1. INTRODUCTION TO TOPIC want access to a new drug. Some people in this position turn to social media outlets to find support from well-connected friends who might be able to help by intervening with ex- ecutives at a company. Sometimes, patients will use social media and news outlets to pub- Suppose you have a disease or illness that can’t licly pressure drug companies into providing be treated. You’re going to get worse. Perhaps the unapproved medication. you’re even dying. There is no drug available in a pharmacy that can help. Maybe your doctor In general, the public is supportive of patients has already prescribed many medications, and who are out of other options, gaining access to nothing has worked. What’s left to do? possible benefits from an investigational drug. However, this method of obtaining unapproved Some patients in this position might learn medication works best for patients who are about a new medication that might help. It’s wealthy, connected, and socially savvy. Pa- still being developed, so your doctor can’t just tients who are well-off and well-connected are prescribe it to you. But you still may be able likelier to have access to better healthcare. The to get to try it. best medical professionals are more likely to be aware of compassionate use, and ongoing Maybe the drug is being tested on volunteers drug development. In fact, there is no reliable who are healthy or in patients who have the online resource for medical professionals to condition or disease or in animals. These tests find which drugs are available for compassion- are known as “clinical trials,” a series of stud- ate use. To find out about compassionate use, ies done to make sure that a new drug is safe, you must have access to someone in the know effective, and either equivalent to or better than about what’s in the development pipeline, or other already-available options. In this case, you being tested in clinical trials. might decide to volunteer for one of the clinical trials in order to try to get the new drug. But, Access is not the only ethical problem raised if you are too sick for the clinical trial, live too by compassionate use. Without patients partic- far away from where it is being conducted, or ipating in clinical trials, we won’t get the data decide you do not want to join the clinical trial needed to prove that a new drug is safe and for fear of being assigned to a placebo arm, you effective. In fact, without people participating in may choose to ask the company developing the clinical trials, the federal Food and Drug Ad- drug to let you use it. This is called “compas- ministration (FDA) won’t have enough data to sionate use” of an unapproved medication or decide whether to approve a new drug, and un- treatment. However, the company developing less it’s approved, a drug can’t be sold or used the new medical product is not required to say in the United States. If fewer people participate ‘yes’ to requests for compassionate use. Some in clinical trials, that means it will take longer drug companies have laid out procedures for to conduct those studies, which means it will “compassionate use” requests. However, these take longer for the FDA to make a decision. This guidelines are often vague and confusing, and could cause a delay for future patients to have sometimes companies don’t follow them. access to new, potentially life-saving drugs.

If you’re sick or dying from an untreatable So, what will happen when it becomes easier disease, you could imagine how badly you’d for patients, who otherwise would be en- rolling in clinical trials, to access the drug in development through compassionate use?

DC 1/27/2020 In using an unapproved drug, device, or treat- fects us all. Even if you are healthy now, you may ment, you are potentially causing more harm someday need a drug that is still in development. than good. It is even possible that you could die prematurely from using an unapproved drug. However, drug development is a long and Even a drug that seems promising in early clinical complex process without a guaranteed posi- trials can act differently in sicker patients, which tive outcome. As you can see from the chart could be the case for many people requesting below, the entire process of drug develop- Compassionate Use. Perhaps if you are getting ment-- from discovering a medicine to finish- sicker every day, and you know that you will ing late stage clinical trials-- can span many probably die anyway, you’re willing to take the years on average. In some rare cases, the pro- risk. Still, compassionate use is a complex issue cess can last twenty years or more. What’s that affects not only the patient, but also drug even more alarming is how unlikely it is that a companies, the drug development process, and drug in development will even make it to the the entire healthcare system. In fact, because market. On average, only 1 in 5,000 new early nobody knows what diseases or conditions they stage potential drugs successfully make it to may someday develop, compassionate use af- the pharmacy shelves.

10,000-15,000 Compounds

Drug Pre- FDA Clinical Trials Discovery Clinical Review Manufacturing

20--100 100-500 1,000-5,000 Volunteers Volunteers Volunteers

Pre-Discovery IND Submitted NDA Submitted

*Source: ACRO

DC 1/27/2020 2. DEFINITIONS agnosis, monitoring, or treatment of a serious disease or condition if the following conditions are met. 1. The person’s physician determines that there is no comparable or satisfactory alternative therapy available to diagnose, Compassionate Use monitor, or treat the person’s disease or Compassionate use describes the treatment of condition, and that the probable risk to the a seriously ill or terminal patient who has ex- person from the investigational product is hausted all possible approved drugs and thera- not greater than the probable risk from the pies. These patients seek access to unapproved disease or condition; investigational drugs as a last resort, often 2. FDA determines that there is sufficient accepting risk that the treatment may not work, evidence of the safety and effectiveness or that it may even do more harm than good. of the investigational product to support its use in the particular circumstance The term Compassionate Use was designed 3. FDA determines that providing the investi- to make clear that the drug was being admin- gational product will not interfere with the istered primarily to help the patient, not to initiation, conduct, or completion of clinical gain data, as in formal clinical trials. However, investigation to support marketing approval sometimes data are collected from people 4. The sponsor (generally the company de- who get drugs through compassionate use. veloping the investigational product for Also, drug companies and others do not like commercial use) or the clinical investigator the term Compassionate Use. After all, if they submits a clinical protocol (a document decline a patient’s request, that makes them that describes the treatment plan for the seem automatically non-compassionate! How- patient) that is consistent with the FDA’s ever, there may be very good reasons to de- statute and applicable regulation for INDs cline a request. For example, the supply of the or investigational device exemption appli- drug-in-development may be so limited that cations (IDE’s), describing the use of the there is already barely enough to go around. investigational product.

So, there are a variety of other terms for Com- Also under FDA’s statute, a sponsor or a phy- passionate Use. The FDA calls it “Expanded sician may submit a protocol intended to pro- Access.” Other terms include “Early Access vide widespread access to an investigational Cohort Programs,” “Single Patient IND,” “Sin- product. In this scenario, FDA will permit the gle Patient Requests,” and “Emergency IND.” investigational product to be made available Internationally, Compassionate Use is referred under a treatment IND or treatment IDE if cer- to as “Named Patient Program,” “Temporary tain criteria are met. Authorization for Use,” and “Special Access Program/Scheme.” A new term that is coming Biotechnology Industry Organization (BIO) into use is “Pre-Approval Access.” Principles. BIO is an industry organization representing FDA Principles for Compassionate Use pharmaceutical and biotechnology companies. A patient may seek individual patient expand- They provide the following principles for Com- ed access (sometimes called single patient passionate Use. access) to investigational products for the di- 1. Considering the clinical situation and need of the patient who seeks access

DC 1/27/2020 2. Determining whether the medicine is under 3. There is sufficient evidence that patients active development can expect a clinically meaningful benefit. 3. Determining whether the patient either is 4. Adequate supply of the investigational med- ineligible for or is unable to participate in icine exists to perform necessary clinical the clinical trial trials as well as sustainably and equitably 4. Assessing the impact of providing access provide access to other patients who do based on the development program for the not have alternative treatment options. product 5. Evaluating the benefit and risk of the pro- Typically, Merck will initiate expanded access posed use of the investigational product programs only in countries where the com- based on currently available data. pany expects to file for regulatory approval. (From the Biotechnology Industry Organization) Generally, once an investigational medicine is approved in a country, the expanded access BIO also recommends that member Com- program will no longer be available. Access panies should make publicly available their to unapproved or investigational medicines general policies regarding how they will eval- must occur according to the requirements of uate requests for expanded access to assist the national regulatory authority where the patients and their physicians in obtaining patient is treated. information about the availability of access. Information should: Criteria for Patient Eligibility a. Include general description of the factors To be eligible for access outside a clinical trial, that will guide the company’s decisions patients must meet, at a minimum, the fol- regarding expanded access lowing criteria: b. Designate a point of contact with whom • Patients must have exhausted all other physicians or patients may discuss their available effective treatments that are ap- requests for expanded access. proved for their condition and must not be eligible to enter a clinical study involving the For example, the pharmaceutical company investigational medicine. Merck posted information about how it makes • Patients must have a disease that is sim- a decision about Compassionate Use on its ilar in type and stage to the indication(s) website. The website states: for which the medicine is currently being studied and for which there is sufficient Merck uses the following guidelines to deter- evidence of efficacy to expect that the mine when and how to make available investi- individual may derive a clinically meaningful gational medicines outside of clinical trials: benefit.

General Criteria for Access to Investigation- Right to Try Laws al Medicines Right to Try Laws allow a patient to ask a 1. The medicine is intended to treat a disease pharmaceutical or medical device company that is life-threatening, or sufficiently seri- for access to an unapproved treatment if the ous and progressive. patient’s condition is terminal, the patient has 2. There is sufficient evidence to expect that the a doctor’s prescription, and the treatment medicine will have an acceptable safety profile requested has passed Phase 1 safety trials. for the specific patient population so that pa- In phase 1 Clinical trials, new treatments are tients are not exposed to unreasonable risks. first tested on people. In a drug trial, the drug is given to healthy volunteers- not patients- to see how much of the drug can be given before

DC 1/27/2020 there are unacceptable side effects. So, the law prevents the production, use, or sale of point of a Phase 1 Trial is to determine a safe unapproved drugs and devices. Because of dosage, and this dosage is used in later trials this, every state with Right to Try laws could on patients to determinate whether a drug is be prosecuted by the federal government. effective at a safe dose. However, some med- However, the government is weary to pun- ications, like cancer drugs, are only adminis- ish these states, because they don’t want to tered to affected patients with cancer in Phase seem “uncompassionate” by taking down 1 trials, as it would be too dangerous to use legislation related to compassionate use. these treatments on healthy volunteers. Regardless of this, 19 states have enacted Right to Try laws, and 21 states are consid- Advocates of Right to Try Laws sometimes ar- ering whether to pass such laws as of May gue that these laws would enable patients to 2015. These laws are sometimes called “Dal- access “later phase” treatments that are not las Buyers Club” Laws, after a movie with approved yet. However, this is not what the that name. (The movie was based on real, laws actually say. The laws say that patients historical events related to a case on AIDS can request treatments that have completed drugs, but is not entirely factual.) Phase 1. This means that people may request access to drugs that have not yet been tested Opening Discussion Questions to see if they work on the disease. 1. In Compassionate Use cases, what role should the FDA play? What about patients Right To Try laws aim to limit the role of the and families? Physicians and medical pro- FDA, suggesting that the agency approval professionals? Drug companies? cess is restrictive, and has slowed the process 2. Who should decide what wins the balance of drug development. However, the track re- between the risks and benefits of a medi- cord of the FDA has been to approve over 99% cine? Why? of applications. They have even designed new 3. What is more important: giving Compas- guidelines to streamline the process, speed up sionate Use to a sick or dying individual, or decisions and improve potential access. streamlining drug development for every patient to have access? Can we find the bal- Right to Try laws may sound like the patient ance between individual and societal rights? has a right to get access to the desired drug or device in development. However, Right to Try Laws do not obligate anyone to provide 3. CASE STUDY: THE EFFECTS OF treatment, provide any payment for treat- SOCIAL MEDIA ment, or require a patient’s insurer to pay for/ provide any resources for travel, lodging, or other logistics necessary for treatment. Even the term “Right to Try” may be misleading, since there is no “right” associated with these laws to guarantee access, without the 1. How do you think social media affects Com- approval of the drug company. passionate Use cases? 2. If you were seeking Compassionate Use, The first right to try law was passed in Colora- would you utilize social media? If so, why do in May of 2014. However, state laws can- and how? If not, why would you refrain? not be passed before federal laws, and federal Case Study: Josh Hardy Josh Hardy is a seven-year-old patient who suf- fered from a life-threatening virus in 2014. His

DC 1/27/2020 virus was an adenovirus, a common virus that When Chimerix decided to protect the pro- is not very harmful to healthy people, but can cess of drug development for Brincidofovir, be fatal to those who are sick. Josh was quite denying Josh access to the treatment, his sick; because he had been diagnosed with mother took to social media, posting a letter cancer as a young child, he’d been exposed to to her Facebook page. She asked if anybody many powerful drugs and treatments, which had connections to Chimerix, and could pos- caused their own problems for his body. sibly help in persuading the company to give Josh Brincidofovir. Josh had been treated with an anti-viral agent called Vistide, but unfortunately, had to cease Seemingly overnight, Josh Hardy’s story blew treatment because the medication was de- up on social media and in the news. There stroying his kidneys. was a massive public outcry against Chimerix. The CEO of Chimerix was contacted by state His physicians had heard of an experimental and national politicians, and even received antiviral drug called Brincidofovir, being devel- some death threats. oped by a company called Chimerix for the treatment of several different viral infections. The company tried to explain the grounds for Josh’s physicians requested that Chimerix its decision. It also pointed to another ethical provide Josh with access to Brincidofovir, but problem: before Josh, some 300 patients had the company had planned to focus solely on requested access to Brincidofovir and been the completion of the drug’s Stage 3 clinical denied. Was Josh different from all these oth- trials. These are the trials in which a drug’s er people, or, if Chimerix gave Josh the drug, safety and efficacy is more formally proven in would they also have to give it to everyone larger clinical trials, providing data which the else who had asked? If so, who would pay for FDA can use to decide whether to approve a this expensive program? (The company nor- drug for marketing. mally can’t charge patients, because it’s illegal to sell a drug before FDA approval; however Chimerix was a small company without lots some compassionate use programs make the of people or money, and it had decided earlier drugs available at the company’s costs with- that it didn’t have the capability to run Phase 3 out any profit.) Trials (which are expensive and involve a lot of work), and provide Compassionate Use at the On March 11, 2014, Chimerix declared that same time. For Compassionate Use, there the company would open a 20 patient clinical is paperwork to be filled out and the compa- trial that would include Josh Hardy. Josh re- ny not only has to provide the drug, but also ceived Brincidofovir on March 12, and left the possibly teach the doctors how to use it. Also, hospital on March 25th, nearly virus-free. the company needs to stay in touch to see if there are side effects, which must be record- ed and reported to the FDA. The following discussion questions are appro- priate for a teacher-directed classroom activity, Here, we arrive at a moral dilemma: should or as group activity. Students could also be Chimerix endanger their ongoing clinical trials asked to write a response or argumentative es- and drug development stages for Brincidofovir say in response to any one of these questions. to make an exception for the life of a seven- year-old? 1. Why do you think Chimerix initially denied Josh Hardy’s request for Brincidofovir? Was it wrong for the company to want to focus

DC 1/27/2020 on getting the drug approved for everyone? not survive. He was the first person to die in How could Chimerix have better handled the United States from Ebola. the situation? 2. Was it wrong for Josh Hardy’s mother to It is unclear whether Duncan was too ill to take to social media? Why do you think her have benefitted from the drug, or if Brincido- efforts were so effective? Do you think any- fovir had contributed to Duncan’s death in any one could have solicited such a public outcry way. Regardless, the story of Duncan’s death in an effort to receive Compassionate Use? circulated rapidly across the country, and the 3. It is clear that the general public wants to public responded. Chimerix’s stock price in- rescue patients like Josh Hardy from their creased after the announcement that Duncan afflictions, and help them circumvent the would receive Brincidofovir, and decreased strict regulations of drug companies like after the announcement of Duncan’s death. Chimerix. Is there a better way to help patients like Josh, while allowing pharma- Compassionate use is often potentially prob- ceutical companies to focus on important lematic for companies; a bad result in the area clinical trials? for which the company is seeking approval 4. What do you need to launch a successful would have to be reported and explained to the social media campaign for Compassionate FDA, which could make the FDA less willing to Use? What kinds of people wouldn’t be able approve the drug. For example, if Josh Hardy to do this? had died, Chimerix would have had to explain why its drug for Adenovirus didn’t work on a 4. CASE STUDY: WHEN THE DRUG FAILS patient with Adenovirus. However, Chimerix had not been looking to develop Brincidofovir for Ebola. Because Adenovirus and Ebola have some similarities, it seemed to doctors that Brincidofovir might work on Ebola as it worked for Adenovirus. However, if the drug did not 1. How could a Compassionate Use treatment work on Ebola, this negative finding would not impact ongoing clinical trials and drug devel- be a problem when Chimerix went to the FDA opment? to try to get Brincidofovir approved, as it was seeking approval for Brincidofovir as a treat- Case Study: Thomas Eric Duncan ment for Adenovirus, not for Ebola. So, in this In September 2014, Chimerix provided a case, the stakes were lower for Chimerix than man named Thomas Eric Duncan with the for many companies grappling with Compas- same experimental antiviral drug that had sionate Use requests. (Remember, those seek- successfully treated Josh Hardy. Duncan was ing Compassionate Use are often quite sick, suffering of a viral infection with no known and thus more likely to have bad outcomes.) cure. This particular viral infection gained an immense amount of media attention; Duncan had contracted Ebola. 1. What are the risks of a small biotech company providing experimental treatment Because there were no standard treatment through compassionate use? Converse- procedures for patients with Ebola, Duncan ly, what could biotech companies gain in gained access to Brincidofovir through Com- providing experimental treatment through passionate Use. Unfortunately, Duncan did compassionate use? 2. Should Thomas Eric Duncan have received Brincidofovir, even though he may have already

DC 1/27/2020 been too ill to survive? Why or why not? 75-year old Roman Catholic priest from Spain 3. How can we alter our expectations for before the supply ran out. experimental treatments through compassionate use, so as to protect ongoing drug Unfortunately, five days after he was evacuat- development? ed from Liberia, Miguel Pajares died. Howev- 4. Why was Chimerix initially unwilling to give er, his death cannot be attributed to the fact Brincidofovir to Josh for his Adenovirus, but that he’d been treated with ZMapp, because surrendered the drug to Thomas Eric Duncan? he was already terminally ill with Ebola when (Answer: Ebola is a contagious Virus that he received the medication. had no known treatment and frequently caused death. So, Thomas Eric Duncan’s The fact that this experimental drug was ad- situation was a public health emergency ministered to non-Africans was widely per- while Josh’s was simply a personal tragedy. ceived as racist. In response, others pointed If Adenovirus had spread from Josh, it likely out that if the drug was given to Africans and would not have made anyone very ill, un- not to Americans or Europeans, it may have less they were already quite sick.) been seen as experimenting upon Africans, a troubling situation which has happened in the past, in the case of the early history of HIV/ 5. CASE STUDY: UNEQUAL ACCESS AIDS drug development.

The Americans had requested access to ZMapp before West African nations, which could have explained why they were initially the sole recipients of this experimental treat- 1. What are some factors that could prevent ment. However, it is puzzling that a 75-year equal access to Compassionate Use? old would be granted this extremely rare treatment; elderly immune systems are much Case Study: The Ebola Epidemic less likely to have the capacity to fight such Although it originated in West Africa, the 2014 an aggressive viral infection, with or without Ebola Epidemic ignited a climate of global medication. Furthermore, it is difficult to mon- panic. There are no approved treatments for itor the effects of an experimental drug when the contagious virus. Ebola spread like wild- the patient has an already weak immune fire throughout West African countries, killing system, and may not be alive for long enough tens of thousands of people. to track the drug’s long-term impact.

Meanwhile, Mapp Biopharmaceutical, Inc. was in the process of developing a possible 1. Why do you think West African countries treatment for Ebola called ZMapp. ZMapp were less aware of ZMapp as a possible had never been tested in humans, and was treatment? Why do you think a 75-year old not a promising solution for ending the Ebola Roman Catholic priest had precedence in epidemic. It could not have been produced receiving ZMapp? Should the elderly be and distributed in large quantities within the discriminated against in the case of Com- time constraints dictated by such a global passionate Use? emergency. However, ZMapp had been ad- 2. ZMapp did not have the potential to end ministered to two American aid workers and a the Ebola epidemic; does this justify the fact that no West African nations received ZMapp?

DC 1/27/2020 3. How can pharmaceutical companies, gov- Caplan, Arthur. “Bioethicist: Experimental ernment officials, and relief organizations Ebola Treatment Endorsed, But Who Gets It?” work together to create more equity for NBC News. 12 Aug. 2014. http://www. Compassionate Use cases? nbcnews.com/storyline/ebola-virus-out- 4. If quantities of a compassionate use drug break/bioethicist-experimental-ebola-treat- are extremely limited, what should be done? ment-endorsed-who-gets-it-n178691

6. CONCLUSION Caplan, Arthur, and Kenneth Moch. “Res- cue Me: The Challenge Of Compassionate Use In The Social Media Era.” Health Affairs Blog. 27 Aug. 2014. http://healthaffairs.org/ 1. List the benefits of Compassionate Use. blog/2014/08/27/rescue-me-the-challenge-of- 2. List the drawbacks of Compassionate Use. compassionate-use-in-the-social-media-era/ 3. Discuss the costs and benefits of the current state of Compassionate Use, drawing Cooley, Tracey. “BIO Principles on Expanded from the definitions and case studies. Access to Investigational, Unapproved Med- icines.” BIOtechNow, 23 April 2015. http:// www.biotech-now.org/health/2015/04/bio- principles-on-expanded-access-to-investigational-unapproved-medicines 1. Should there be Compassionate Use? Why Gaffney, Alexander. “’Right to Try’ Legislation or why not? Tracker.” Regulatory Affairs Professionals 2. In what ways can we improve Compas- Society 24 June 2015. http://www.raps.org/ sionate Use? Are there underlying ethical Regulatory-Focus/News/Right-to-Try/ issues that cannot be solved? Merck Sharp & Dohme Corp. “Expanding Pa- tient Access to Merck’s Investigational Medi- 7. REFERENCES AND ADDITIONAL cines.” Merck. http://www.merck.com/ RESOURCES about/views-and-positions/access-to- medicines/home.html Bateman-House, Alison. “Drug Development, Compassionate Use, and Adverse Events: A U.S. Food and Drug Administration. “Learn Cautionary Tale.” Bioethics.net. 8 Mar. 2015. About Expanded Access and Other Treatment http://www.bioethics.net/2015/03/drug-de- Options.” . velopment-compassionate-use-and-ad- U.S. Food and Drug Administration verse-events-a-cautionary-tale/ Web. http://www.fda.gov/ForPatients/ Other/ Caplan, Arthur. “Bioethicist: Ebola Treat- ment to West Is Troubling, Bad Science.” NBC News. 11 Aug. 2014. http://www.nbc- Acknowledgements news.com/storyline/ebola-virus-outbreak/ This module was prepared by Samantha bioethicist-ebola-treatment-west-trou- Scheer with support from Arthur Caplan, Ali- bling-bad-science-n178026 son Bateman-House, and Carolyn Plunkett of the Division of Medical Ethics in the New York University School of Medicine.

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