Patient Rights and Access to Investigational Drugs and Medical Devices: Is There a Problem With the Current System?

1. Patient Rights and Access to Investigational Drugs and Medical Devices: Is There a Problem With the Current System? Bruce Patsner, M.D., J.D. Research Professor University of Houston Law Center September 24, 2008

2. Disclaimer • The medical and legal opinions in this talk are those of the author alone, and do not represent the views of the University of Houston Law Center, the United States Food and Drug Administration, or any other physician, attorney, academic, or government official

3. Question: Is there a “problem” that needs a solution? • Is there any hard evidence that the current system does not work for: Unapproved experimental medical devices? Unapproved investigational drugs? What are current options, and what are the limitations?

4. The Abigail Alliance Litigation • Legal issue: do terminally ill patients have a constitutional right to unapproved investigational drugs? • A patient interest group sued FDA in federal court • A 22 year old girl with a progressive head and neck cancer wanted access to Iressa and to Erbitux, drugs not approved at the time • Father brought suit, later joined by experienced anti-regulatory group Washington Legal Foundation • Wanted access to drugs after Phase I testing; WLF acknowledged that in rare cases patients might want access to drugs in Phase I testing as well

5. What was being proposed in Abigail Alliance as a solution? • Would have enjoined (prevented) FDA from barring sale of investigational drugs to terminally ill cancer patients after only Phase I testing • No change in informed consent requirements even though no real safety or efficacy data known • ?waiver of liability for physicians to be worked out later

6. Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach 445 F.3d 470 (2006) • Brought in federal district court in District of Columbia in 2003 after FDA failed to respond to Citizens Petition • Case dismissed by federal district because “no constitutional right” existed so there was “failure to state a valid claim” • On appeal to D.C. Circuit Court of Appeals 2-1 decision IN FAVOR OF plaintiffs rocks the medical community. LOTS of writing on this in the throw-away journals. • Arguments raised by FDA against, and consumer groups for, were both legal, medical, and practical

7. Arguments advanced by plaintiffs: Legal ♦Denying access to drugs deprived patients of right of “self-defense” or “self-preservation” ♦Due process clause protects the right of such patients in late stages of disease to decide for themselves whether to assume the risks of unapproved drugs. Denial denied patients’ 5th Amendment due process right to life, liberty, property ♦Dying cancer patients had unique risk:benefit calculus, and Supreme Court has already ruled that patients have a right to die by refusing medical treatments (Cruzan case). These patients have “special latitude” ♦NO privacy rights/ bodily integrity arguments raised, interestingly enough

8. Arguments advanced by Plaintiffs: Practical • Terminal cancer patients should have ability to opt for new treatment that meets a lower evidentiary hurdle than that required for new drug marketing • Current regulatory system does not provide special provisions based on risk of injury or death from disease • Current system doesn’t work because patients cannot find appropriate clinical trials, live too far from research centers, or do not meet eligibility criteria. Also, sometimes their physicians refuse to patient’s request compassionate use

9. Arguments Raised by FDA and Others in Defense: Legal • Constitutional right to unapproved drugs was rejected firmly by Supreme Court in Rutherford v U.S. 1980 (laetrile case) • No Constitutional right to drugs even if physicians want patients to get it too and even if state laws approve (Gonzales v. Raich 2005 medical marijuana case) • Prescription drugs generally cannot be sold (marketed) until they are approved, according to amended 1938 Federal FDCA • Informed consent and tort liability issues

10. Arguments Raised by FDA and Others in Defense: Practical • Right claimed by Abigail Alliance underestimates toxicities/risks, and overestimates success rate, of these drugs. There is no more unique risk: benefit ratio for terminally ill cancer patients than other desperately ill patients who’ve exhausted options • Would undermine entire drug approval process: no incentive to participate in Phase II and III trials, even if not placebo-controlled • Would create black market, and subject ill vulnerable patients to fraudulent claims • Will never get accurate safety and efficacy data for the drugs • Patients will “doctor shop” in order to make an end run around physicians who legitimately believe the drug is either too dangerous, has no chance of working, or both • There ALREADY ARE multiple programs in place that work and are readily accessible. Lots of options for docs/patients

11. The 2-1 D.C. Circuit Court of Appeals Decision: Holdings • Terminally ill patients do have a right to potentially life-saving experimental drugs even when very risky • Throughout most of U.S. history government has not blocked access to these drugs • Patients have a right to make life-or-death decisions free from government interference • There is a due process right which can be inferred from the Cruzan decision and a patients right to REFUSE medical treatment • Dissent: no history of a right to experimental drugs. FDA has a rational basis for ensuring there is acceptable evidence about risks and benefits of drugs • For a while, this decision WAS the law in the U.S.

12. En banc decision by the entire D.C. Circuit Court of Appeals Followed • 8-2 against Abigail Alliance • Court holds that Alliance’s claimed right is not a fundamental right (such as a due process right), and therefore only subject to rational basis, not strict, scrutiny. • Burden for Alliance was thus to show that FDA’s current policy bears no rational relationship to a legitimate state interest • Appeal (writ of certiorari) rejected by the U.S. Supreme Court. Case dead. The bottom line is that there is… • No constitutional right of the terminally ill cancer patient to experimental drugs which have only completed Phase I testing and are awaiting FDA approval • Decision consistent with S. Ct. precedent

13. United States v. Rutherford 442 U.S. 544 (1979) • Terminally ill cancer patients and their spouses brought this action to enjoin the government from interfering with the interstate shipment and sale of Laetrile, a drug not approved under the FDCA. • Section 505 of the Act prohibits interstate distribution of any “new drug” unless an NDA is approved by Sec’y of HEW as supported by substantial evidence of the drug’s safety and effectiveness. • This is still the law. • This case was the precedent the first decision, and the last decision, cited

14. Access to investigational drugs can differ, but it’s not due to FDA • No real data to back up plaintiffs’ claims that access to investigational products is a big problem for cancer patients. Abigail’s oncologist was at Johns Hopkins, for instance. • There is a problem of availability for products from small biotech companies – may not have enough of the product, or enough money to provide it for free outside of a clinical trial. That is not (just) FDA’s problem. • Little literature on the difference in patient access to large molecule biologics from small companies versus getting drugs from big Pharmaceutical companies such as Pfizer

15. General results from access to drugs just out of Phase I • Chance of dying from drug treatment: 1/200 • Chance of significant clinical response: 2-4% • These responses are virtually always partial responses of short duration • Chance of serious morbidity from treatment: 20-50% • NO ONE is ever cured by treatment with investigational drugs • IND: Investigational New Drug. Approval required to allow a company to ship a drug. That’s why the court decisions all talk about “interstate shipping”

16. New Drug Approval Today • Pre-clinical (Phase 0) testing in animals takes 1-3 years, at least two species, to support preliminary work in humans • IND filed to begin investigation in humans. IND can be filed after Phase 0, I, or during Phase I or II. No rule except that preclinical testing must be completed first. Phase I – examines drug toxicity and pharmacology, MTD in 20-100 healthy human volunteers Phase II – drug tested in more patients with variety of diseases. Takes months-years Phase III – testing in hundreds-thousands with best, specific disease(s) drug most effective in from Phase II data. Trials takes years, can cost up to $60M+ Results of 1-2 Phase III trials support NDA application

17. Recent Changes to the Drug Approval Process 1983-1993 • 1983 -FDA formalizes various exemptions to IND application process by allowing treatment and emergency use INDs to expand patient access to experimental drugs for those with no alternative therapy. Result of AIDS crisis. • Subpart E established variety of measures to expedite review and speed clinical trials, including use of only 1 study for approval and use of Phase IV post-marketing testing after allowing drug on market • Accelerated approval, including approval based on predicted benefit via use of surrogate endpoints in clinical trials (though must still prove clinically) • 1992 – expedited review and parallel track program specific for HIV/AIDS therapies

18. Available FDA Mechanisms for Accessing Unapproved Drugs • Original language of section 505(i) of the FDCA was expanded in 1962 solely to authorize clinical trials designed to obtain safety and efficacy data sufficient to justify FDA approval of an NDA • FDCA never authorized/intended use of investigational drugs for ill patients outside of a clinical trial. But… • Although FDA has not allowed “commercialization” of an unapproved new drug since 1938, it has often ignored the rule that investigational drugs cannot be used for treatment purposes • SO LONG AS there was a clinical trial ongoing and patients were not charged

19. Obtaining Investigational Drugs for Therapy: What’s Available? • Use for treatment, not just for clinical trial • General term is “expanded access” – there is no single term or program. Some overlap. • An exception to general ban on commercial use of investigational drugs. Formalized in §561 of FDAMA in 1997, provides specific statutory authority for expanded access to investigational drugs • Now are more than a dozen routes to access investigational drugs • FDA now considering changing rules, mostly to CLARIFY what’s out there under what would be a new Subpart I to 21 C.F.R. 312 • Would also clarify when you could charge for this

20. 4 Basic Ways, Different Names • Enroll in a clinical trial sponsored by an institution or drug company • Obtain Compassionate exemption from physician participating in trial; doctor requests drug from the company • Patient can write directly to the company to get it • Physician can write to FDA to get approval for use by having doctor request either single patient or emergency use IND • We’ll elaborate on these and others

21. Investigational New Drug (IND) Access for Therapy • Individual Patient IND • Emergency Use IND • Treatment IND • Parallel Track IND • Group C Cancer Treatment IND • Open Label IND • Compassionate Use IND • Orphan Drug IND • Tropical Drug IND • Special Exception IND

22. Individual Patient IND • Single patient exception to allow use of drug outside of the protocol of the approved IND. FDA practice since 1962. Can be submitted by a drug manufacturer as an amendment to existing IND, or by physician or individual investigator on behalf of a patient • Legal Basis for this exception in Smith v. Shalala, (D.D.C. 1996): court held that FDA could allow a terminally ill cancer patient to get access to unapproved drugs undergoing investigation • Formalized in 1997 under §561(b) of FDAMA: any person may ask, through a physician, for access to an investigational drug for treatment of a serious disease or condition if meet 4 criteria 1. there is no satisfactory therapeutic alternative available 2. a protocol exists or will be submitted 3. FDA determines that providing it will not interfere with clinical investigations to support NDA approval 4. there is sufficient evidence of safety and effectiveness to support the use of the investigational drug • Note: Would seem to eliminate anything without some Phase 2 data

23. Emergency Use IND • §561(a) of FDAMA codifies another basic FDA practice. • Authorizes shipment of investigational drugs or devices for the treatment of a serious disease or condition in emergency situations • Exempt from prior IRB approval, as no time to do so • MAY BE exempt for informed consent, such as in an ICU situation/unconscious patient, but usually informed consent is needed for emergency use IND • IRB approval must eventually be obtained, and an IND submitted afterwards • Physician requests this as well

24. Project BioShield Act of 2004 • Expands emergency use • Adds §564 to FDCA to allow FDA to authorize use of an unapproved new drug during a declared domestic, military, or national security emergency • Done twice by FDA at request of Pentagon, to allow emergency use of anthrax vaccine by military personnel

25. Treatment IND • §561(c) of FDAMA • Permits use of investigational drug under a treatment protocol (aka “expanded access protocol” for treatment of a serious or life-threatening disease • Grew out of peak of AIDS crisis. Final rules appeared in 1987 • DOES allow sponsor to charge for this, but not more than is necessary to recoup “costs” • This has fallen into disuse when CMS and third party payers refused to reimburse for any drugs used under a treatment IND on the ground that it represented experimental use • Also fell into disuse when AIDS community used it to get unapproved meds that compromised efficacy of known medications. This is no longer a problem: AIDS community now the first to insist that experimental meds with unproven efficacy be used inside of clinical trials because now have good meds

26. Parallel Track IND • Unlike others, this is not codified in CFR but was announced in Federal Register on May 21, 1990 • Started in 1990 at impetus of NIH because of AIDS crisis • Permits use of investigational drugs by people with AIDS and HIV-related diseases who are both unable to benefit from existing standard therapies AND unable to participate in ongoing clinical trials • BUT, an investigational new drug cannot be released into this program before patient enrollment in an FDA-approved Phase II clinical trial for that drug is initiated

27. Group C Cancer Treatment IND • Since 1976 NCI has furnished qualified physicians the most promising investigational drugs, called Group C drugs, to treat their patients outside of ANY clinical trial • These drugs appear in a master file submitted to FDA • NCI includes on this list ONLY those drugs it concludes are likely to obtain NDA approval in near future. This is a big limitation • This is an informal program, also not codified • Appears in Memo of Understanding between FDA and NCI published in 1979 • Under program, NCI asks FDA for permission to ship the investigational drug to the selected investigator • Patients are not charged • These are virtually always only drugs NCI is developing themselves. You are NOT requesting this from a drug company

28. Open Label IND Not codified • Usually just continuation of the treatment arm of a clinical trial that has concluded • Unlike others, do collect safety and efficacy data and report to FDA under the IND • Like a single patient IND but allows FDA to process requests for multiple individuals through a single general request from a drug sponsor

29. Compassionate Use IND • A broad, undefined term which sort of encompasses others. Not much difference from open label IND • Applies to situations in which the use of an investigational new drug for patient therapy does not fall within any other expanded access IND program • FDA has VERY liberal view of this when there is a clear medical need • Again, big push for this arose out of AIDS crisis but now has broad applications in cardiology, neurology, etc…

30. Orphan Drug IND • Prior to enactment of the Orphan Drug Act of 1983 under Pres. Reagan, orphan drugs seldom proceeded from an IND to an approved NDA • This was thus a common mechanism • Much less so now, since companies now have real financial incentives to develop orphan drugs, and even greater incentive to see if there is a potential off-label use (e.g. Epogen)

31. Tropical Drug IND • FDA has long permitted drugs for tropical diseases to be the subject of clinical trials in the U.S. but until recently rarely approved NDAs on the grounds there was no need for such drugs in this country. Less so because of travel • Nevertheless, a tropical drug IND is pretty much a permanent state. Rarely go on to NDA

32. Special Exception IND • This comes from the sponsor, not the physician or the patient • When an individual is ineligible to enroll in a clinical trial of an investigational drug, sponsor can request that FDA permit a special exception from the protocol to permit excluded individual to receive treatment • Not in any FDA guidance or regulation, but it does happen. Data excluded from reporting.

33. Emergency Research • In 1996 FDA established regulations governing the narrow circumstance under which emergency clinical research may be conducted without informed consent, e.g. because of a life-threatening condition for which there is no available alternative and the patient is unconscious • 60+ INDs submitted for this between 1996 and 2006. No final rule yet

34. Importation of Investigational New Drugs for Personal Use? Status… • Again, originally a result of desperate AIDS and cancer patient efforts • Somewhat conflicting regulations: FDA won’t detain unapproved new drugs brought into U.S. for personal use at same time prohibiting them because of concerns about safety and fraud • FDA uses enforcement discretion to overlook so long as no intent to sell, and the use of the product is identified • A HUGE problem now with Internet, which FDA has not even begun to engage • Morphs over into the issue of importing approved drugs from Canada, which arose because of the cost of prescription drugs in this country.

35. Any “holes” in these programs for unapproved drugs? • Between the time FDA initially determined the NDA for Erbitux to be approvable and the time FDA approved the drug for marketing, the manufacturer received 8500 requests for compassionate use. • No data in FDA data bank on how often this was granted • No real data on how often patients can’t get unapproved investigational drugs. • No real data on whether ANY of the previously described exemptions to IND regulations so that patients can access experimental drugs are “too slow” • In general, CDER/CBER/CDRH at FDA act on these immediately • Any data from Methodist or M.D. Anderson ever published? • Patients always have final option of engaging in “medical tourism”

36. New proposals now being considered by FDA to expand access to investigational drug and biologic products • FDA now can authorize emergency use via telephone, fax, or email • Drug sponsor or physician obligated to later file a written submission complying with proposal, and to be added to IND file, within 5 days • Intermediate size populations where anticipate continuing protocol. Need some evidence of safety and efficacy first • New proposal will be much more specific about what charges may be covered • Not a minor issue: example: providing Provenge or other biologicals can easily cost a company $50,000 or more/ patient. Biotech drug development differs.

37. What about unapproved biological drugs and biologics? • Covered by the Public Health Services Act (PHSA), not FDCA • Under control of CBER at FDA, not CDER • Examples: Gene therapy, cancer vaccine products • General mechanisms are the same, all come under exemptions from IND requirements for investigational new drugs

38. Medical Devices • General approval routes • Expedited review • Product Development Protocols – somewhat unique to devices • Investigational devices, and routes for exemptions to requirements

39. New Medical Device Approval • Route depends on the class (I, II, or III) of the medical device • Because approval requirements for marketing vary depending on the device class • Class I  right to market • Class II some to market, others via 510(k) clearance • Class IIIvia 510(k) if substantially equivalent to predicate device on market before 1976 MDA to FDCA, otherwisePMA • Standards for approval may be easier than for drugs

40. Expedited Review • Exists for both drugs and devices to get them to market faster • Intended for drugs or devices to treat or diagnose a life-threatening or irreversibly debilitating disease or condition, and meet these criteria: • Device represents breakthrough technology • No approved alternative exists • Offers significant advantages over what’s on the market • Availability of the device in the best interests of the patient Applications receive priority review, and are public

41. Product Development Protocols (PDP) • A unique mechanism for devices, separate from PMA application, and no equivalent program exists for NDAs for drugs • It’s a protocol to establish safety and effectiveness in humans based on a protocol (hypothesis, objectives, endpoints) BEFORE the study starts. Contains bench info, animal testing, maybe some data in humans • FDA experience with this is limited; rarely used • Focus on established technologies: spinal cages, pacemakers, new Pap technology

42. Investigational Devices and Patient Access to Same • For drugs there is the IND process • For devices there is the IDE process: the Investigational Device Exemptions • Formal investigation of experimental devices aside, there are situations which arise where a patient will need a device which has not yet been approved

43. What Is An IDE? • A mechanism for conducting clinical safety and effectiveness evaluations for a device that has not yet been approved for marketing in the U.S. either a PMA • A way to get devices being tested to patients in need. For class III devices this will be before safety and efficacy data have been fully evaluated by FDA • Requirements for different exemptions vary

44. Purpose of an IDE • As with INDs for drugs, allows lawful shipment of an unapproved device across state lines for the purpose of conducting human clinical studies. • It’s like an IND • And, what we are talking about is patient access before approval. Usually for class III devices • Encourages the development of useful devices consistent with public health, safety, and ethical standards • Sets procedures for conducting human clinical trials with new devices, and for access to devices outside of the trial as well. • There are requirements for an IDE application

45. IDE Application Requirements • Similar to those of IND: IRB, consent forms, institutions, training manual, all investigators, investigational plan • Investigational plan: purpose, protocol, risk analysis, device description, statistical analysis plan, monitoring process, how safety and efficacy will be measured • Statement re: won’t charge more than necessary to recover costs

46. Unlike Drugs, There Are Broad Exemptions from IDE Requirements, aside from HDE • 510(k) cleared devices investigated in accordance with FDA-cleared indications for use • Veterinary devices • Devices intended and labeled solely for research with laboratory animals • Devices undergoing consumer preference testing which does not put subjects at risk and is not designed to determine safety or efficacy, i.e. device poses “no risk” • Custom devices for one patient UNLESS goal is to evaluate safety/efficacy for commercial application • Diagnostic devices if test non-invasive, introduces no energy into the patient and is not used for diagnosis without confirmation by another established diagnostic procedure or test

47. Humanitarian Device Exemption (HDE) • Devices for the treatment or diagnosis of diseases affecting less than 4,000 patients in U.S. per year • Analogy to drug situation before passage of Orphan Drug Act Criteria: • Device not otherwise available • No alternative device • Exempt from showing it works (effectiveness requirement) • Only need safety evidence from non-clinical studies • Example: twin-twin transfusion device

48. Threshold Requirements for FDA to Approve an HDE • Device will not expose patients to unreasonable or significant risk of illness or injury • Probable benefit outweighs the risk of injury or illness • Taking into account the probable risks and benefits of currently available devices or alternative forms of treatment

49. HDE Specifics • IRB approval required • Informed consent NOT required • Subject to GMPs • Cannot make a profit • 75 day review by FDA • HDE approvals by FDA 2001-2004: 28 • Examples approved: fetal bladder stent, heart value, bladder stimulation device • For these products there was limited clinical information available, mostly bench/animal/cadaver testing, as well as knowledge about the natural history of the disease without the device

50. Other IDE Types • Full IDE for a Significant Risk Device • Abbreviated IDE for a non-significant risk device • Treatment Use IDE • Emergency Use IDE • Compassionate Use IDE • Continued Access IDE Clearly, similar to those for access to investigational drugs which are part of INDs