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1 King & Spalding May 22, 2014

1 King & Spalding May 22, 2014 Presentation for Clinical and Translational Science Center ─ University of California, Davis Health System

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1 King & Spalding May 22, 2014

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1 King & Spalding May 22, 2014 Presentation for Clinical and Translational Science Center ─ University of California, Davis Health System Expanded Access to Investigational Drugs for Treatment Use Beverly Lorell, MD Michael Petty Preeya Noronha Pinto Kim H. Roeder Washington, D.C. Washington, D.C. Washington, D.C. Atlanta 1 (202) 383-8937 1 (202) 626-2951 1 (202) 626-5527 1 (404) 572-4695 blorell@kslaw.com mpetty@kslaw.com ppinto@kslaw.com kroeder@kslaw.com

2 Beverly Lorell, MD 1 (202) 383-8937blorell@kslaw.com Michael Petty 1 (202) 626-2959 mpetty@kslaw.com Preeya Noronha Pinto 1 (202) 626-5547 ppinto@kslaw.com Kim H. Roeder 1 (404) 572-4675 kroeder@kslaw.com

3 Expanded Access Programs: A brief primer for clinical research centers and physician investigatorsAccess for individual patients, intermediate-size patient groups, and large patient populationsRoles of the FDA, physician, healthcare institution (including the IRB), and manufacturer What to expect from the pharmaceutical manufacturer Consideration of CMS NCD clinical trial policies and Expanded Access ProgramsConsiderations for healthcare providersAnticipating and navigating challenges Topics for Discussion

4 Expanded Access to Investigational Drugs for Treatment UseA Brief Primer of the FDA Expanded Access Regulations, as amended in 2009

5 Program regulated by FDATo improve access to investigational drugs for the treatment of patients with a serious or immediately life-threatening disease or condition who do not have comparable or satisfactory alternative therapeutic options and who may benefit from such therapiesIntent is treatmentDiffers from use of an investigational drug in a clinical trial where the primary purpose is research (i.e., the systematic collection of data)Method of obtaining accessFDA approval of an Expanded Access Submission, which is a type of an Investigational New Drug (IND) application (i.e., a new IND or protocol amendment to existing IND) What are Expanded Access Programs?

6 Consolidated requirements (Subpart I of 21 CFR Part 312)Three distinct categories of patient accessIndividual patients, including for emergency use Intermediate-size patient populationsBroad populations Treatment IND (a new IND) or Treatment Protocol (protocol to an existing IND) General standards, as well as specific standards based on the size of population and seriousness of the diseaseRequirements for obtaining accessSafeguards, including IRB review, informed consent, and reporting requirements to FDAKey Features of the Amended Regulations

7 For period of Oct. 13, 2011 – Oct. 12, 2012:Total received by CDER: 940. Total approved: 936.Individual patients: Received: 908. Approved: 904. Emergency use INDs: Received: 289. Approved: 287.INDs (not emergency use) : Received: 498. Approved: 496.Protocols (amendment to existing IND): Received 121. Approved 121. Intermediate-size populations (protocols – amendment to existing IND): Received: 10. Approved: 10.Broad populations (Treatment Protocols – amendment to existing IND): Received: 7. Approved: 7. The majority of submissions (87%) were new Expanded Access INDs for individual patients submitted by physicians. Source: Presentation of Richard Klein, Office of Health and Constituent Affairs, FDA. CBI Expanded Access Conference, Philadelphia, PA, July 17 – 18, 2013. FDA’s Recent EAP Track Record

8 FDA must determine that:Patients to be treated have a serious or immediately life-threatening illness or conditionNo comparable or satisfactory alternative therapy existsPotential patient benefit justifies the potential risks of the treatment, and those risks are not unreasonable in the context of the disease or condition being treatedProviding the drug will not interfere with or compromise clinical investigations that could support marketing approval for the Expanded Access indicationGeneral Requirements (21 CFR 312.305)

Definitions matter! Expanded Access Programs

“A stage of disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.” (21 CFR 312.300)“Immediately Life-Threatening Disease or Condition”

“A disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible, provided it is persistent or recurrent. Whether a disease of condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.” (21 CFR 312.300)“Serious Disease or Condition”

12 Physician must determine that probable risk does not exceed that of the disease for the individual patientFDA must deem that patient cannot obtain access under another type of IND or protocol, and that “potential risks are reasonable” Emergency useFDA may authorize without written submission, followed by written submission within 15 working daysSafeguards Sponsor is often the physician who submits an IND for treatment use, in roles of investigator and sponsorGenerally limited to single course of treatmentSubmission of end-of-treatment report to FDA, including all adverse effectsMonitoring not generally requiredIndividual Patients (21 CFR 312.310)

13 Generally up to 100 patientsDemonstration of need for investigational drugDrug being developed, but patient cannot participate in clinical trialDrug not being developed (e.g., rare disease)An approved or related drug is no longer marketed or not available (e.g., drug shortage with foreign version of drug)Sufficient evidence that drug is safe for proposed dose and duration relative to size of exposed populationPreliminary clinical evidence of effectiveness or plausible pharmacologic effect Additional safeguardsExplanation of why drug cannot be developed or, if drug is being developed, why patients cannot be enrolled in a trial for the use Monitoring, as well as annual report for review by FDAIntermediate-Size Populations (21 CFR 312.315)

14 Drug is being investigated in clinical trial to support marketing, or all trials have been completedCompany is actively pursuing marketing approvalSufficient evidence of safety and effectiveness for the useSerious Disease: Evidence from phase 3 trial or compelling data from phase 2 clinical trialsImmediately Life-threatening Disease: Available evidence provides reasonable basis to conclude drug may be effective for the use and would “not expose patients to an unreasonable and significant risk of illness or injury” (could consist of evidence more preliminary than phase 2 or 3 trials) Additional safeguards30-day wait period for FDA review, or earlier notification of FDA approval Monitoring, as well as annual report for review by FDA Large Populations: Treatment IND/Protocol (21 CFR 312.320)

15 Drugs used in FDA-approved Expanded Access Programs are investigational drugs, even though the drugs are being used for treatment, not research.All FDA human subject protections are applicable, including Institutional Review Board (review and approval, including emergency use) – 21 CFR Part 56Protection of Human Subjects (informed consent) – 21 CFR Part 50FDA authority to issue Clinical Holds, based on safety and reporting requirements (adverse event reports, annual reports) – 21 CFR Part 312 Role of the IRB

Expanded Access: Challenges for IRBs 16In compliance with 21 CFR Part 50, how can the 8 Basic Elements of informed consent cited in 21 CFR 50.25(a) be incorporated?As example, element (1) requires a statement “that the study requires research, an explanation of the purposes of the research…”FDA has not provided guidance or examples of informed consent templates appropriate for Expanded AccessTo what depth should IRB review what is and isn’t known about the investigational drug?Is it best practice for IRB to have template for informed consent for Expanded Access Programs? Should templates differ for the 3 categories of Expanded Access?

17 Question: Can the same drug be used at the same institution more than once? If so, is prospective IRB review required for the subsequent expanded access emergency use of the same drug?FDA’s answer (See May 2013 FDA draft guidance):“There can be more than one expanded access emergency use of the same drug at the same institution.FDA expects that, for expanded access uses authorized under the emergency procedures, there typically will not be time to obtain prior IRB approval of the use. In such cases, the emergency use must be reported to the responsible IRB within 5 working days of initiation of treatment (21 CFR 56.104(c)). Once an investigational drug is used in an emergency situation without prior IRB approval, any subsequent uses of the investigational drug at that same institution would ordinarily require prior IRB review and approval (21 CFR 56.104(c)). However, when prior IRB review and approval is not feasible for a subsequent expanded access emergency use at a particular institution, FDA does not intend to deny the subsequent request for emergency use due to lack of time to obtain prospective IRB review, as long as that use will be reported to the IRB within 5 working days of initiation of treatment.”Emergency Use in Expanded Access: IRB Review

18 Responsibilities of licensed physicians who administer or dispense an investigational drug under Expanded AccessObligations of an investigator, includingAdverse event reporting to sponsorEnsuring IRB review and informed consentRecords, including accurate case histories and drug disposition An investigator who also submits a new IND for Expanded Access for an individual patient is considered a sponsor-investigator and must comply with the FDA requirements of both sponsors and investigators. Role of the Physician (21 CFR 312.305)

19 Decide whether to provide the investigational drug under an Expanded Access ProgramDecide whether to charge for the drug, pursuant to 21 CFR 312.8 Expanded Access for Individual PatientsIn response to a physician’s request for expanded access to an investigational drug as the sponsor-investigator, Company is not required to provide the drugIf company agrees to provide drug to a physician as sponsor-investigator, company provides physician with written authorization for FDA to reference the company’s existing IND If company decides to provide the EA submission to FDA for the single patient as the sponsor, company submits a protocol amendment to an existing IND that it holds. Role of the Manufacturer

20 As sponsor of an FDA-approved IND, obligations includeIND safety reports to FDAAnnual reports to FDAEnsuring that the licensed physicians are qualified to administer the investigational drug for Expanded Access useMonitoring the physicians as investigators (only for Expanded Access Programs for intermediate-size and broad populations)Providing information to physicians to minimize risk and maximize potential benefits (including Investigator Brochure)Maintaining an effective IND for the Expanded Access useRecords, including drug dispositionOther sponsor responsibilities under 21 CFR 312 may apply Role of the Sponsor (21 CFR 312.305) Manufacturer (or Sponsor-Investigator)

Sequence – Expanded Access Programs for Individual Patients Physician and Patient Patient meets regulatory criteria Patient educated about process Manufacturer Agreement to provide drug Permission to refer to its IND FDA Physician submits Individual Patient IND Approval IRB Review and approval Informed consent

Patients, physicians and healthcare providers are often confused about Expanded Access ProgramsUnderstanding the amended regulations and providing accurate and transparent information helps to lower the risks Considerations

Common issues of misunderstanding for patients, physicians and healthcare providers“Compassionate Use” – a potentially misleading term Manufacturer is not required to provide investigational drug or provide it free of chargePhysician always incurs regulatory obligations as investigatorObligations as sponsor-investigator, if the physician is holder of the Individual Patient IND Potential medical costs may be incurred by the patientIncluding costs of the drug and medical expenses for injuryUse of drug at stage of early and incomplete understanding of its safety risks: Possible overestimation of benefit and underestimation of riskKey Take-Aways

24 Understanding the Pharmaceutical Manufacturer Perspective on Expanded Access Programs (EAPs)

25 Inherent Tensions and Need for Balance Make information on process/requirements available; process transparent Update information Monitoring (required for Intermediate Size and Broad Population EAP) Effort/burden Costs, including whether to charge for the investigational drugEAP Challenges and Risks for Pharmaceutical Manufacturers

EAP Challenges with PhysiciansChallenges with physiciansEmergency requests Wanting access outside the program Wanting full indemnities Wanting promises of no cost to patients Wanting funding Locations; number of sites Qualified in this role? Not properly fulfilling investigator role Not wanting the program to end Pros/cons of company-sponsored submissions 26

EAP Challenges regarding FDAChallenges with FDA Tremendous discretion Evidence of safety Can get different decisions from FDA Information on whether drug is being developed for population to be treated and if not, why/under what circumstances could it be EAP vs. open-label safety study Risk of interference with clinical investigations“Significant number” of similar requests can result in FDA request for more sponsor involvement. EAP = less push for FDA to approve? 27

EAP – Additional ChallengesOther Challenges Physician, FDA, and drug sponsor are key parties, but other stakeholders exist Distraction from clinical trials/applicationSupply issues How to say “No” 28

29 Important programs for potentially beneficial patient accessAppropriate to inform of program informationCompany websiteCommuniques with patient advocacy organizationsPress releases Many patients today involved with internet research; patient forums, etc. FDA websites EAP Communications - Challenges

30 Safety and efficacy are not proven Drug is unapproved, and may not be approvedCan technically create “labeling”, although no approved label exists ≠ traditional scientific exchange or investor relations communicationsQuestions from HCPsQuestions from PAOsQuestions from patients Separation of venues, other information on the product & programCommunications - Challenges (cont’d)

Pharma Company Communications - Challenges (cont’d)No promotional context/claims allowedLow-keyed factual toneNot suggest drug will be approvedCharging for drugThird party administrator experienceAwareness of program is goal Program focus, rather than studies, data, or disease educationClinicaltrials.govOther indicia of promotional context/tone 31

SummaryRegulators increasingly cynical of corporate intent Commercial role/involvement“Prepping the market” concernImplied claims; demand creationChemGenex untitled letter for Omapro Bottom LinePatient access info must remain the “out front” message versus “promotional” messages 32

312.6 Labeling of an investigational new drug.(b) The “label” or “labeling” of an investigational new drug shall not bear any statement that is false or misleading in any particular and shall not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated. 33

312.7 Promotion of investigational drugs.(a) Promotion of an investigational new drug. A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug. This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution. 34

Consideration of CMS National Coverage Determination on Clinical Trials 35

36 To be covered under Medicare, drugs must be (1) safe and effective and (2) reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body memberMedicare typically does not cover:Unapproved drugsApproved drugs for investigational uses (i.e., uses that are off-label and not “medically accepted”)Limited Exceptions (e.g., Group C cancer drugs, drugs covered through NCDs, LCDs, or individual coverage decisions) Medicare policies regarding coverage of investigational drugs are typically considered in the context of clinical trials—although these policies are not directly applicable to Expanded Access Programs, they are instructiveDoes Medicare Cover Investigational Drugs?

37 Medicare’s “Clinical Trial Policy”Applies to items and services reimbursable under Medicare Part A, Medicare Part B, and Medicare Advantage (MA)In order for routine costs to be covered, a clinical trial must be a “qualified” trial through one of three pathways:Meet certain “qualifying criteria” (not yet established by CMS)Automatically qualifiedFunded by NIH, CDC, AHRQ, CMS, DOD, VA directly or through one of their centers or cooperative groups orConducted under an IND reviewed by FDA or IND-exemptCoverage mandated under an NCD ( e.g., Coverage with Evidence Development policy where item/service is covered by Medicare only in the context of a clinical trial)NCD for Routine Costs in Clinical Trials

38 All items and services that are typically covered absent a clinical trial (in both experimental and control arms)Required solely for the provision of the investigational item or servicee.g., investigational drug administration costs such as infusion supplies and nursing timeRequired solely for the clinically appropriate monitoring of the effects of the item or servicee.g., additional lab tests to monitor for side effects of the investigational drugRequired solely for the prevention of complicationsNeeded for reasonable and necessary care arising from the provision of an investigational item or service, including for the diagnosis or treatment of complications NCD: What IS Covered?

39 The investigational item or service itself, unless otherwise covered outside of the clinical trialIs the investigational use of an FDA-approved drug a “medically accepted” off-label use? If so, it may be covered outside of the clinical trialItems and services provided solely to satisfy data collection and analysis needs and that are not used in the direct clinical management of the patiente.g., monthly CT scans (solely to collect data) for a condition usually requiring only one scanItems and services customarily provided by the research sponsors free of charge for any enrollee in the trialCoinsurance/deductibles NCD: What IS NOT Covered?

Part D drugs are not subject to the NCDPart D coverage is typically limited to FDA-approved drugs used for a medically-accepted indication (i.e., supported by compendia)In clinical trials, an example of drugs that may be covered under Part D are FDA-approved drugs used as a control or as part of combination therapy (unapproved drugs would not be covered)Coverage also depends on the formulary of the patient’s Part D plan 40 Outpatient Prescription Drugs under Medicare Part D

Medicare coverage policies do not specifically address the situation where unapproved/investigational drugs are used for treatment purposesTwo paradigms: (1) “Reasonable and Necessary” Standard and (2) Clinical Trial Policy (NCD)Under either paradigm, the investigational drug itself is usually not covered, but other items and services associated with clinical care and/or treatment of the patient are likely coverede.g., costs of infusion of an investigational drug and overnight observation services to monitor the patiente.g., costs of hospital stay to monitor/treat cardiac complications resulting from use of the investigational druge.g., follow-up visits to physician office for examination of potential side effects from investigational drug regimen 41 What Is Covered in Expanded Access Programs?

42 Look to Medicare clinical trial policies to determine likely Medicare coverage of Expanded Access Programs—consult your Medicare Coverage Analysis document prepared for the clinical trialInvestigational drugs used in Expanded Access Programs are typically not covered by MedicareProviders/patients may be responsible for costs, depending on whether a manufacturer charges for the investigational drugOther treatment costs associated with the use of investigational drugs in Expanded Access Programs are typically covered by MedicareIncludes investigational drug administration costs, diagnosis/treatment of complications, monitoring of side effectsItems/services performed solely for data collection or analysis, provided free of charge, or not ordinarily covered by Medicare are typically not covered by Medicare in Expanded Access Programs Key Take-Aways

43 Anticipating and Navigating Hidden Risks for Healthcare Providers

Provider Responsibilities -- Expanded AccessAccording to the FDA, most Expanded Access requests are individual patient treatment IND requests, including emergency requestsThese types of Expanded Access requests present unique challenges to an institution attempting to apply its regular investigational drug processesA physician (not a corporate sponsor) may be acting as the sponsor-investigator, bearing substantial responsibility for the entire process (patients can access an investigational drug only through a licensed physician, regardless of the sponsor).Expanded Access is focused on treatment, not research; but all review processes referenced are couched in terms of research. “Emergency” truncates advance documentation and IRB review. 44

Expanded Access – Individual Patient: Challenges for HospitalsPatient expectations and dire medical circumstancesNo clinical research agreement with corporate sponsor; how to address: CostsResources available for patient in event of harmIndemnificationRegulatory compliance 45

Expanded Access – Challenges for HospitalsThe Draft Guidance recognizes that FDA allowing recovery of a cost does not mean that FDA controls reimbursement policy for government programs or private health plansFDA does not attempt to direct from whom costs are recovered (usually, the patient/third party payor)For purposes of disclosure, the patient must be informed of responsibility for these costs in the event they are not covered by a third party payorHospital and IRB must manage expectations that the institution will absorb these costs (subject to charity care policies, if applicable); and also protect patients from exploitation 46

Expanded Access – Hospital/IRB Resources to Manage UncertaintiesWill the informed consent process in this context be adequate to protect the physician and hospital if the investigational drug provided under Expanded Access is not effective, or worse yet, is injurious to the patient?“ … patients who are candidates to receive investigational drugs under Expanded Access programs … should be afforded a rigorous informed consent process that effectively communicates the risks and potential benefits of any investigational therapy to be used for treatment use in a way that does not raise false expectations about a positive outcome from treatment and makes clear what is unknown about the drug.” 74 Fed. Reg. 40900, 40920 (Aug. 13, 2009) 47

Expanded Access – Elements of Informed Consent (21 CFR § 50.25)21 CFR § 50.25(a)(1) & (3):A statement that the study involves research, an explanation of the purpose of the research and the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which are experimental.A description of any benefits to the subject or to others which may reasonably be expected from the research. Expanded Access Consent:Note – Must address duration of treatmentNote: Treatment under an Expanded Access mechanism is not intended primarily to develop data that could be used to benefit other patients. See 74 Fed. Reg. 40900, 40920 (Aug. 13, 2009) 48

Expanded Access – Duration of TherapyPer the Draft Guidance, individual patient access is generally limited to a single course of therapy for a specified duration, unless FDA expressly approves multiple courses or chronic therapy. FDA may authorize multiple courses or chronic therapy when the circumstances of the treatment are well-defined and reasonable in light of the available evidence to support use of the drug. Draft Guidance, Q9.“FDA … does not typically authorize access of unspecified duration at the discretion of the treating physician.” Draft Guidance, Q9. FDA may require monitoring if use is for an extended duration. 49

Expanded Access – Elements of Informed Consent (21 CFR § 50.25)21 CFR § 50.25(a)(4):A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous. Expanded Access Consent:No other acceptable medical options:There is no FDA-approved drug available to treat the patient’s condition Approved drugs are not available, have not worked or cause intolerable side effectsThe patient is not eligible for a clinical trial that might helpNote: What about alternative unapproved treatments? 50

Expanded Access – Informed Consent: Risks and Benefits // FDA ObservationsQuery: Is there a tendency to overestimate the benefit or underestimate the risk of access to the unapproved drug, for patients with serious/life-threatening diseases who have no alternatives?Limited information about safety and effectiveness is available for Expanded Access drugs, particularly if still in the early stage of study Safety more important than efficacy in this contextLow evidentiary burden when considering use of an investigational drug for a patient with an immediate, life-threatening condition Unknown risks and limited information: Patient may experience some benefit, no effect or harm But note that toxicity may worsen patient’s already dire situation – e.g., increase pain or accelerate death without offering an increase in patient’s quality of life 51

Expanded Access – Emergency Situation: Challenges for HospitalsFDA may authorize Expanded Access for an individual patient without a written submission if an emergency requires the patient to be treated before a written submission can be made. 21 CFR § 312.310(d). Access may begin on verbal authorization (telephone) by the reviewing FDA official. Draft Guidance, Q17.Written submission to be made within 15 working days Appropriate “when treatment … must occur within a very limited number of hours or days.” “FDA intends to scrutinize emergency requests and to authorize access for such requests only when the situation is a true emergency.” Draft Guidance, Q11. 52

Expanded Access – Emergency Situation: Challenges for HospitalsTypically, for Expanded Access authorized under emergency procedures, there will not be time to obtain prior IRB review.The emergency use must be reported to the IRB within 5 working days of initiation of treatment. 21 CFR § 56.104(c) (exemption from IRB review for emergency use of test article).There can be more than one Expanded Access emergency use of the same drug at the same institution. Draft Guidance, Q11.. “Once an investigational drug is used in an emergency situation without prior IRB approval, any subsequent uses of the investigational drug at that same institution would ordinarily require prior IRB review and approval …” but FDA will not deny further emergency access if prior IRB review is not feasible. Draft Guidance, Q11. 53

Checklist of Information Needed from Physician: Expanded Access for IndividualIn case of emergency, IRB should require (5 days) – Any information provided to FDA to obtain verbal authorizationDetails of telephone/verbal authorization by FDATreatment protocol (including dosing, frequency, administration)Informed consent form used or justification for exceptionExpanded Access submission made to FDA within 15 days Consider encouraging prior IRB review (requires some flexibility in the meeting schedule and resources to act quickly) Consider IRB retrospective review of emergency access: Compliant? 54

Expanded Access – Hospital/IRB Resources to Manage UncertaintiesPolicies and ProceduresExplanation and sequence of Expanded Access regulatory process (web-based)Checklists for review of Expanded Access requests, particularly for individual patients and emergency situationsIRB process for review of Expanded Access requests and documentation of emergency useIdentified (and trained) contact personsTraining for IRB, other staff, physicians who may seek Expanded AccessTemplates:Request forms, IRB review Consent forms and review process: Adapt for treatment scenario of Expanded Access 55

56 Healthcare & FDA Life Sciences Roundtable Thank you! Q & A

57 Additional Information and ReferencesUseful FDA resources about Expanded Access Programs (EAP)Brief summary: Regulatory history of EAPBrief summary: When a manufacturer may charge for an investigational drug in an EAP

Resources for Today’s Discussion “Expanded Access to Investigational Drugs for Treatment Use”74 FR 40900, August 13, 2009.Amends 21 CFR Parts 312 and 316.“Charging for Investigational Drugs under an Investigational New Drug Application”74 FR 40872, August 13, 2009. Amends 21 CFR Part 312.“Guidance for Industry. Expanded Access to Investigational Drugs for Treatment Use–Qs & As. Draft Guidance.” May 2013.“Charging for Investigational Drugs Under an IND–Qs & As. Draft Guidance.” May 2013.

1987 – FDA amends the Investigational New Drug (IND) regulations at 21 CFR Part 312 to provide access for broad patient populations under a Treatment IND/Protocol 1997 – Congress enacts FDAMA, making Expanded Access part of the statute and specifying when an individual patient may obtain an investigational drug for treatment use2006 – FDA issues proposed rule to further amend 21 CFR Part 312 and address limitations Only addressed access for large groups of patients Did not define levels of evidence required for different categoriesMight have resulted in inequitable patient access 2009 – FDA issues final rule amending existing regulations, effective October 13, 2009Background of Expanded Access

60 A manufacturer may charge for an investigational drug under an IND, including drug provided under Expanded Access. 21 CFR 312.8Must request authorization from FDA and demonstrate:Sufficient enrollment in any ongoing clinical trial needed for marketing approval to assure FDA that it will be successfully completed as planned;Evidence of adequate progress in drug development for marketing approval;Information specifying drug development milestones the sponsor plans to meet in next year; andAmount to be charged recovers only direct costs of manufacturing, shipping, and handling; for Expanded Access, may also charge for costs of monitoring, complying with FDA reporting requirements, and other administrative costs. If company is not the sponsor of the Expanded Access IND, it is not required to obtain authorization from FDA to charge for the investigational drug. Charging for the Investigational Drug under Expanded Access