Preapproval Access - Exploring the Landscape for Compassionate Use, Expanded Access, Right-to-Try, and How Companies...

Focus report published by Avalere Health LLC, February 2016

Avalere’s Take

NEED TO KNOW

Increased public attention on preapproval access and evolving stakeholder expectations is driving the need for life science companies to create ethical, patient-centered preapproval access policies and develop transparent ways to allow appropriate access to their investigational products while managing the inherent risks in doing so.

AVALERE’S TAKE

This Policy 360 Focus Report on Preapproval Access delivers:

• An overview of compassionate use in the United States,
• FDA’s expanded access program,
• Right-to-Try state laws, and
• How companies can prepare and take action.

Compassionate Use in the United States

Stakeholders have long debated the issue of “compassionate use” or whether and how best to provide patients access outside of clinical trials to investigational products¹ not yet approved for any indication by the Food and Drug Administration (“FDA” or “the agency”). While participating in clinical trials allows many patients access to investigational products, for those who are ineligible for or cannot join a clinical trial, access to these products is difficult, and they may not have the time to wait for FDA approval.
Today eligible patients can receive these products outside of clinical trials through FDA’s “Expanded Access” program. In addition, many states are passing “Right-to-Try” laws hoping to give eligible patients an easier way to obtain these products. Federal legislators are also introducing legislation aimed to improve “preapproval access” – a term referring to patient access to investigational products, regardless of how access is obtained. And in response to public pressure on the manufacturers of these investigational products to allow access, companies are developing formalized, publically-accessible, preapproval access policies, and piloting innovative ways to ethically address patient need.

How did we get here?

While many factors contributed, social and popular media played a large part.
In early 2014, intense media attention thrust preapproval access into the spotlight when a family’s attempts to gain access to an investigational drug forced one company to provide their product to the 7-year old patient in critical condition.² His family attributes his recovery to the investigational drug he received.³ Many other patients’ families and advocates have used targeted media campaigns to pressure companies to release products. The expansion of social media in the last decade has further enhanced the visibility of questions concerning preapproval access.⁴ Several websites such as change.org include pages dedicated to preapproval access social media campaigns and almost all are petitions directed at manufacturers.
The scrutiny intensified after widespread media coverage questioned how two Americans gained access to an experimental product after contracting the Ebola virus in Liberia.⁵ Following these events, a World Health Organization (WHO) panel⁶ made an unprecedented decision, albeit in the context of a public health emergency⁷, announcing that it was ethical to “offer unproven interventions with as yet unknown efficacy and adverse effects, as potential product or prevention” for people infected in the current Ebola virus disease outbreak in West Africa.
In addition, patients continue to take an ever increasing role in their healthcare decisions. Patients, family caregivers and advocacy organizations demand that product development become more patient-centered, that manufacturers meaningfully engage patients and family caregivers throughout drug discovery and development, and take into account their perspectives, needs and desires.
As awareness of preapproval access as a potential option⁸ increased, complaints from both patients and healthcare providers surfaced regarding a lack of transparency (from both FDA, who allows the access, and product manufacturers, who have to agree to release the investigational product) and difficulty navigating the system. FDA has responded with efforts to streamline its expanded access program to decrease the burden of requesting access.⁹ In addition, states have debated, introduced and many have passed so-called “Right-to-Try” legislation, aiming to offer patients additional avenues, outside of FDA’s expanded access program, to obtain investigational products in certain circumstances.
This increased public attention on preapproval access and evolving stakeholder expectations is driving the need for life science companies to create ethical, patient-centered preapproval access policies and develop transparent ways to allow appropriate access to their investigational products while managing the inherent risks in doing so.

FDA’s Expanded Access Program
FDA’S PUBLIC HEALTH MANDATE: THE INHERENT TENSION BETWEEN THE POPULATION AND THE INDIVIDUAL

FDA’s mandate is to protect and promote public health. The agency’s mission was first to ensure safety, and later both safety and effectiveness of health interventions through the use of rigorous scientific methods and standards.¹⁰
In the vast majority of cases, drug sponsors demonstrate that their investigational product is safe and effective by conducting clinical trials comparing the safety and efficacy of their drug to a placebo (no drug) or the current standard of care. For pivotal trials (those Phase III studies conducted to demonstrate safety and efficacy), clinical trial participants ideally consist of a representative sample of patients so that the results of the study can be extrapolated to the larger patient population that will take the drug after approval. The primary purpose of these studies is research (supporting approval of the drug), not individual treatment of the study participants (although that might be an outcome). In essence, enhancing the public’s health (by approving new therapies) relies on the ability of the drug to be approved.
In contrast, while the outcomes of giving patients investigational products outside of clinical trials may be informative, the primary goal of preapproval access is treatment of those specific individuals and not research. As discussed more below, there is a risk that giving patients’ preapproval access will impair a sponsor’s ability to get the drug approved and ultimately prevent or delay the drug from getting to the larger patient population waiting. For example any adverse event, even in a patient who would not normally qualify for the drug because their condition does not match that proposed for the product, will be included in the final marketing application being considered by FDA. This inherent tension between the interests of the individual in their own treatment and the larger patient population (and/or the public as a whole) in getting the product FDA approved and on the market is what makes preapproval access so challenging.

FDA’S EXPANDED ACCESS PROGRAM IN PRACTICE

While FDA has permitted informal access to investigational drugs and biologics for a long time, the HIV/AIDS epidemic of the 1980s changed the landscape. Activists challenged FDA’s drug approval process, complained that the Agency’s focus on safety was delaying access to life-saving products, and petitioned to gain access to investigational antiretroviral drugs.¹¹ FDA’s formal program for preapproval access, called “expanded access” (sometimes called “early access”), originated in 1987 with a rule change to explicitly provide for treatment use of investigational drugs under an Investigational New Drug (IND) Application “product protocol” or “product IND”.¹² In 1997, the Food and Drug Administration Modernization Act of 1997 (FDAMA) gave the Agency specific statutory authority to allow access to investigational products and laid out eligibility criteria for emergency situations, individual patient access and access for larger groups.¹³
In 2009, FDA amended its IND rules governing expanded access¹⁴ to make investigational drugs more widely available, and the agency responded to criticisms regarding lack of transparency in expanded access decision-making and potential inequality of access among different types of patients and patients suffering from different conditions.¹⁵ These revisions clarified the requirements, streamlined the process at FDA, and created a clear pathway for different sizes of patient groups – (1) individual patients, including emergency access for a patient in critical condition, (2) intermediate size groups (generally up to 100 patients), and (3) large groups (treatment use).¹⁶
Table 1 outlines the key eligibility requirements for all types of expanded access uses.

Sources: 21 USC 360bbb; 21 CFR Part 312 Subpart I; FDA Draft Guidance Expanded Access to Investigational
Drugs for Treatment Use – Qs & As, May 2013
IND = Investigational New Drug

As listed in the additional criteria for specific expanded access uses in Table 1, FDA requires increasing evidence of safety and effectiveness as the size of the patient population in the expanded access trial increases.
Figure 1 illustrates FDA’s expanded access process for a request from a physician on behalf of an individual patient (non-emergency). Drug sponsors can also request expanded access of their investigational products. In addition to providing access to patients who do not qualify for on-going clinical trials of the investigational drug, the program can also allow patients to obtain access to a drug that is not being developed or to an approved drug for patients who cannot obtain access because the drug’s availability is limited by a risk evaluation and mitigation strategy (REMS).¹⁷

Physician requesting access for an individual patient (non-emergency)
Numbers designate, in usual order, the key steps
IRB = Institutional Review Board

FDA approves almost all of requests it receives for expanded access. In fact, from October 13, 2009 to September 30, 2015, the agency reported granting over 99% of the expanded access requests it received (7,252 out of 7,291).¹⁸ The vast majority of requests are for individual patients (as opposed to intermediate and large groups of patients).

State Right-to-Try Laws

MANY STATES HAVE PASSED RIGHT-TO-TRY LAWS

Patients, physicians and other stakeholders have voiced their frustration with the FDA’s expanded access process, calling it too burdensome and time-consuming. Incorrectly citing FDA as the major roadblock to bringing investigational drugs to patients, the Goldwater Institute crafted proposed statutory language for use in each state for what they called “Right-to-Try” bills.¹⁹ These bills aim to legislate a new pathway for patient access to investigational products independent of FDA to protect “the fundamental right of people to try to save their own lives.”²⁰
Currently, twenty four states have enacted Right-to-Try laws, and in another twenty four states and the District of Columbia Right-to-Try bills have either been introduced or passed, see Figure 2.

KEY RIGHT-TO-TRY LAW PROVISIONS

According to the Goldwater Institute, terminal patients “should have the option of accessing investigational drugs which have passed basic safety tests, provided there is a doctor’s recommendation, informed consent, and the willingness of the manufacturer of the medication to make such drugs available.”²¹ While the Right-to-Try bills differ somewhat across states, key provisions the bills share include the following:

• Eligible patients are defined as having a terminal illness that has considered all other FDA-approved treatment options.
• Eligible patients must have been given a prescription or recommendation by a physician for the investigational product and informed consent in writing for the use of the investigational product.
• Investigational drugs, biologics or medical devices must have successfully completed Phase I of clinical development and remain under investigation in a clinical trial.
• Physicians, providers and in some cases, hospitals, are protected from losing their medical licenses and Medicare certification based solely on their recommendation of an investigational product to an eligible patient.
• The manufacturer of an investigational drug, biologic or device can, but is not required to, provide an investigational product, with or without compensation, to strictly defined eligible patients.
• Private insurers and government payers can, but are not required to, cover the cost of the investigational product.
• Any state official, employee or agent of the state is prohibited from attempting to block access of an eligible patient to an investigational product and/or such interference is a crime.
• No private right of action against the manufacturer of an investigational drug, biologic or device or any other person or entity involved in the care of an eligible patient for any harm caused to a patient resulting from the use of the product as long as manufacturer or other person has exercised reasonable care.

KEY DIFFERENCES BETWEEN RIGHT-TO-TRY AND FDA’S EXPANDED ACCESS PROGRAM

Critics of Right-to-Try legislation cite three key characteristics of Right-to-Try laws that distinguish them from FDA’s expanded access program: (1) they only apply to the terminally ill, (2) they allow access to products with only very limited safety data, and (3) they reduce patient protections. In addition, state law only governs that state.

• Right-to-Try laws only address terminal patients: While FDA’s expanded access program requires eligible patients to suffer from a “serious or immediately life-threatening disease or condition,” most Right-to-Try laws require patients to be terminally ill, excluding those with progressively debilitating serious diseases.
• Right-to-Try laws only require drugs to have completed Phase I trials: Phase 1 data alone give little to no information about the benefits of a drug. Relying only on minimal safety and no efficacy data, critics wonder whether it is ethical to give these products to patients and with such little (if any) information about risks and benefits, is it possible for patients to give adequate informed consent
• Right-to-Try laws lack provisions for FDA and IRB oversight: Access under Right-to-Try laws do not require the approval of or oversight by either FDA or an Institutional Review Board (IRB), although they do require some form of informed consent from patients. Critics argue this reduces patient protections to the detriment of patients.²² Among other things, FDA can institute a clinical hold on an expanded access trial (i.e., stop the trial) if the agency identifies a safety issue. And IRBs ensure the ethical treatment of patients treated with investigational products under FDA’s expanded access program. Who will ensure ethical product of patients under Right-to-Try considering the lack of IRB oversight? Is FDA expected to intervene if issues arise?

WILL RIGHT-TO-TRY LAWS HAVE ANY IMPACT ON PATIENT ACCESS?

It is too early to know whether Right-to-Try laws will impact patient access. Some have said that they will use Right-to-Try to provide access to their products²³, however the legal standing of these laws is open to question.²⁴ In addition, given that these Right-to-Try laws do not require manufacturers provide access to their investigational products, it is unclear how Right-to-Try will be more successful than FDA’s expanded access program at enabling patients to access drugs from manufacturers.
This may be especially challenging given that the Right-to-Try process created in the states explicitly does not include FDA. Manufacturers will likely be wary of providing drugs for preapproval access in the absence of FDA’s blessing and oversight.²⁵ And the possible reasons manufacturers decline to provide investigational products, such as dwindling supply, costs of providing access, and/or fears of delaying or derailing FDA approval of their drug, still exist for Right-to-Try. For these reasons, it is difficult to see how these bills will expand access and meet the expectations and hopes of patients.

How Companies Can Prepare and Take Action

Currently, very few companies have publically available preapproval access policies. Some have policies, but do not share them publically. Others have no policy in place at all. And still others have disparate policies throughout the company, and would like to formalize a cohesive preapproval access policy and principles to guide their decision-making.
Given the increased public attention on preapproval access, enhanced patient engagement in drug development, approval and access, and evolving stakeholder expectations, now is an opportune time for life science companies to consider creating (or evaluate and revise current) ethical, patient-centered preapproval access policies and develop transparent and fair ways to allow appropriate access to their investigational products.

INNOVATE WAYS TO ALLOW APPROPRIATE ACCESS

Leading with new ways to approach preapproval access is Johnson and Johnson (J&J), who collaborated with the New York University Langone Medical Center (NYULMC) to create an independent review panel called the Compassionate Use Advisory Committee (CompAC).²⁶ The CompAC consists of a group of 10 bioethicists, patient representatives, and medical experts.²⁷
In this pilot program, the CompAC evaluated preapproval access requests globally for J&J’s drug Darzalex™ (daratumumab), used to treat refractory multiple myeloma.²⁸ The CompAC received anonymized requests for access, and after assessing each request, offered recommendations that J&J would consider but did not have to follow. The aim was to create a consistent, fair, unbiased, transparent way to decide preapproval access requests. Once Darzalex™ received FDA approval in November, 2015, CompAC stopped reviewing requests for the US, but continues to consider ex-US requests for the drug.²⁹ And CompAC may start reviewing requests for other drugs.³⁰
Some life sciences companies may struggle with disparate policies, procedures and inconsistent decisions across the organization. Whether it’s an independent group or an internal group, having a formalized policy and central procedures will help reduce
variation across the company and its portfolio of drugs, and enable timely responses when access to their preapproval drugs are sought by patients and their health care providers.³¹

CONCLUSIONS: THINGS TO CONSIDER FOR AN ETHICAL, PATIENT-CENTERED PREAPPROVAL ACCESS POLICY

The following lists some points for manufacturers to consider when developing their preapproval access policies³²:

• You need a preapproval access policy: even if the policy is that you cannot grant access to anyone.
• Develop your policy early in product development: be prepared before you get requests. Policies can always be changed as circumstances change.
• Be transparent: make your policy publically accessible and easily findable on your website. Confirm the site is user-friendly.
• Be clear on how to contact your company: Set up one phone number or email address to take requests and questions. Explain if the patient or the physician should contact you with a request.
• Manage expectations: tell requesters when you will get back to them with an answer (have a set timeframe for response).
• Educate about your policy: are there stakeholders who should know of your policy (e.g., patient advocacy groups or clinicians conducting clinical trials for you)?
• Create a standard intake form for those seeking access: leave out anything that is not necessary and may bias decision-making (e.g., anonymize requests).
• Engage patients as advisors to help you develop a patient-centered policy: also keep continuous engagement with patients to solicit feedback to revise the policy or procedures as needed.

¹ In this paper we use the term “approved” to denote approved or licensed for marketing by FDA. In addition, we use the terms “products” and “drugs” to denote both drugs and biologics. We do not discuss devices in this report.
² Usdin S. How Chimerix, FDA grappled with providing compassionate access to Josh Hardy. BioCentury March 31, 2014; 7-9, available at: http://www.biocentury.com/biotech-pharma-news/regulation/2014-03-31/how-chimerix-fda-grappled-with-providing-compassionate-access-to-josh-hardy-a7 (last accessed Feb. 19, 2016).
³ Kroll D. Josh Hardy Going Home After Getting Chimerix Anti-Viral Drug. Forbes July 17, 2014, available at: http://www.forbes.com/sites/davidkroll/2014/07/17/josh-hardy-going-home-after-getting-chimerix-anti-viral-drug/ (last accessed Feb. 19, 2016).
⁴ See e.g., Caplan A, Moch K. Rescue Me: The Challenge Of Compassionate Use In The Social Media Era. Health Affairs Aug. 27, 2014, available at: http://healthaffairs.org/blog/2014/08/27/rescue-me-the-challenge-of-compassionate-use-in-the-social-media-era/ (last accessed Feb. 19, 2016).
⁵ Hayden EC, Reardon S. Should experimental drugs be used in the Ebola outbreak? Nature News 2014; DOI: 10.1038/nature.2014.15698
⁶ World Health Organization. Media Centre. WHO to convene ethical review of experimental product for Ebola, available at: http://www.who.int/mediacentre/news/statements/2014/ethical-review-ebola/en/ (last accessed Feb. 19, 2016).
⁷ Hayden EC. Ebola declared a public-health emergency. Nature News 2014; DOI: 10.1038/nature.2014.15689
⁸ In addition to access to the drug, the product must be appropriately administered in the correct setting of care and the patient monitored and report back to FDA. Access to the drug does not mean that the cost of the care is covered.
⁹ FDA Draft Guidance Individual Patient Expanded Access Applications: Form FDA 3926, February 2015, available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM432717.pdf (last accessed Feb. 19, 2016).
¹⁰ In 1938, Congress enacted the Federal Food, Drug and Cosmetic (FD&C) Act, which required that a drug be proven safe before it can be sold to the public. In 1962, the enactment of the Kefauver-Harris Drug Amendments Act added an efficacy requirement such that a drug must be shown to be safe and effective before it could be marketed.
¹¹ Amorosa V, Tebas P. Is It Time to Rethink the Expanded-Access Programs for HIV Infection? J Infect Dis 2007; 196(7):974 – 977.
¹² 21 CFR part 312. (52 FR 19466, May 22, 1987).
¹³ FDAMA Public Law 105-115, amended the Federal Food, Drug and Cosmetic Act, section 561 (21 U.S.C. 360bbb).
¹⁴ 21 CFR Parts 312 and 316
¹⁵ FDA Final Rule, Expanded Access to Investigational Drugs for Treatment Use, 74Fed Reg 40900, August 13, 2009.
¹⁶ FDA Final Rule, Expanded Access to Investigational Drugs for Treatment Use, 74Fed Reg 40900, August 13, 2009. See also FDA Draft Guidance Expanded Access to Investigational Drugs for Treatment Use — Qs & As, May 2013, available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351261.pdf (last accessed Feb. 19, 2016); FDA Draft Guidance Charging for Investigational Drugs Under an IND - Qs & As, May 2013, available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351264.pdf (last accessed Feb. 19, 2016).
¹⁷ FDA Draft Guidance Expanded Access to Investigational Drugs for Treatment Use — Qs & As, May 2013, available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351261.pdf (last accessed Feb. 19, 2016).
¹⁸ FDA website, Expanded Access INDs and Protocols, available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/INDActivityReports/ucm373560.htm (last accessed Feb. 19, 2016).
¹⁹ Corieri C. Everyone deserves the Right-to-Try: empowering the terminally ill to take control of their treatment. Goldwater Institute Policy Report, Feb. 11, 2014, available at: https://goldwater-media.s3.amazonaws.com/cms_page_media/2015/1/28/Right%20To%20Try.pdf (last accessed Feb. 19, 2016).
²⁰ Id.
²¹ Id.
²² See e.g., Rubin R. Experts critical of America’s right-to-try drug laws. Lancet Vol. 386 October 3, 2015 1325, available at: http://thelancet.com/pdfs/journals/lancet/PIIS0140-6736(15)00393-1.pdf (last accessed Feb. 19, 2016).
²³ See e.g., BioCentury. Box: Neuralstem's plans, June 30, 2014; Usdin S. Demanding Right, BioCentury Nov. 16, 2015.
²⁴ One issue is whether Right-to-Try laws are constitutional given federal law exists governing preapproval access. See e.g., Richardson Elizabeth. Health Policy Brief: Right-to-Try Laws, Health Affairs, Updated April 9, 2015, available at: http://healthaffairs.org/healthpolicybriefs/brief_pdfs/healthpolicybrief_136.pdf (last accessed Feb. 19, 2016).
²⁵ Usdin S. Demanding Right, BioCentury Nov. 16, 2015.
²⁶ Miseta E. J&J hopes to change the paradigm on compassionate use review. Life Science Leader. Jan. 1, 2016, available at: http://www.lifescienceleader.com/doc/j-j-hopes-to-change-the-paradigm-on-compassionate-use-review-0001 (last accessed Feb. 19, 2016).
²⁷ Id.
²⁸ Meyer E. A pioneering partnership to bring fairness to “compassionate use” requests. NYULMC, Department of Public Health news release, Jan. 7, 2016, available at: http://www.med.nyu.edu/pophealth/newsevents/awards-recognition/pioneering-partnership-bring-fairness-compassionate-use-requests (last accessed Feb. 19, 2016).
²⁹ Id.
³⁰ Id.
³¹ Miseta E. J&J hopes to change the paradigm on compassionate use review. Life Science Leader. Jan. 1, 2016, available at: http://www.lifescienceleader.com/doc/j-j-hopes-to-change-the-paradigm-on-compassionate-use-review-0001 (last accessed Feb. 19, 2016).
³² Some points derived from statements of Art Caplan and Alison Bateman-House from NYULMC during Avalere’s webinar How to Develop Compassionate Use Policies, December 15, 2015. See also Meyer E. A pioneering partnership to bring fairness to “compassionate use” requests. NYULMC, Department of Public Health news release, Jan. 7, 2016, available at: http://www.med.nyu.edu/pophealth/newsevents/awards-recognition/pioneering-partnership-bring-fairness-compassionate-use-requests (last accessed Feb. 19, 2016); Usdin S. Scaling Compassion. BioCentury, Nov. 16, 2015; Commentary: The equitable pathway. BioCentury, Mar. 31, 2014.