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This is a commentary on the proposed regulations as they relate to the practice of oncology. It does not address the more complex ethical and legal issues surrounding the rights of patients to investigational drugs, which it is anticipated will be examined by the courts. The stated purpose of the proposed regulations is to provide broader access to INDs for seriously ill patients when there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease, although the term seriously ill patient remains undefined. Immediate, life-threatening disease, for the purpose of the regulation, is defined as “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.” Patients in this group, having exhausted standard treatments, would be the most expected petitioners for the expanded access program but also the least likely to escape premature death. The FDA, however, now indicates 3 categories of patients who might obtain investigational drugs under the expanded access regulation. Two of these, the individual application and the open-ended treatment protocol, are accommodated by existing regulations, which will be replaced by the proposed regulations. The open-ended category historically was identified with the term compassionate IND. This process, for example, permitted many patients with ovarian cancer preapproval access to paclitaxel when there was substantial data available on both toxicity and efficacy. The FDA has now proposed a third category, a new intermediate group of between 10 patients and 100 patients who, for various reasons, may not meet the eligibility criteria for ongoing, formal study protocols or who may be averse to participating in required, correlative studies. The addition of the intermediate category could provide a new resource both for patients and for physician investigators at institutions. The open-ended and intermediate categories in particular could generate data that may be of substantial value in selecting both specific patient populations and the most appropriate doses and schedules if the agent receives approval by the FDA.

The claim has been made that patients outside of specialized centers and patients with serious illnesses other than cancer did not have the same access to investigational drugs under expanded-access protocols as patients with cancer diagnoses. In addition to facilitating access to investigational drugs for seriously ill patients who have no comparable or satisfactory alternatives, the FDA has to make a determination that the potential benefit justifies the potential risks of treatment and that these are not unreasonable in the context of disease. Furthermore, it has to be established that providing the investigational drug will not interfere with the overall conduct of clinical trials, either before or during accrual. This aspect may be difficult to assess unless it is monitored carefully by the FDA on an ongoing basis. Under the projected regulations, a physician from any geographic location and possibly without experience in the use of newer generations of oncologic drugs would submit a request on the patient's behalf. The request also could be submitted by the sponsor of the investigational drug. In some instances, the sponsor and physician may be the same individual, although, in an institutional setting, it is likely that the institution will assume the role and responsibilities of sponsor in relation to IND studies. Depending on the category for which expanded-access is applied, the amount of supporting documentation required for submission to the FDA will vary. The physician would have to determine that the patient has a serious or immediate, life-threatening condition and that no other effective treatment is available. Treatments that might supplant an expanded IND access conceivably could include surgical or radiotherapy procedures; commercially available drugs that currently are not approved for a specific condition, but their use and benefit are supported by reasonable data; or active protocols for the experimental drug of interest and provided the study drug is accessible logistically to the patient. The widespread use of hospital-based or multidisciplinary tumor boards could be helpful in determining the appropriateness of a new treatment being recommended outside of the standard guidelines. The institutional review board (IRB), in reviewing the application prior to its submission to the FDA, must determine whether there is clinical equipoise (essentially, an agreement among experts in the field that there is no accepted standard treatment) and that risks of harm are balanced by potential benefit to an individual patient or to the group. A specific make-up of the IRB for the purpose of reviewing these applications, however, is not defined clearly by the proposed regulation. In some locations, IRBs may lack adequate representation in oncology disciplines, and many of the INDs, particularly biologics, are complex compounds with negative interactive potential, either by interfering with drug activity or by enhancing toxicity, when combined with commercially available drugs. The proposed regulations state that the physician and/or sponsor applying for expanded access will be responsible for providing the monitoring and safety information in a timely fashion. Institutions and others that routinely conduct clinical trials with oncologic agents likely will have inplace highly efficient and transparent research infrastructures that include advanced levels of continuous monitoring. The availability of expertise and resources would be no less relevant for individual patient-expanded access. However, there is no guidance about how adherence to the standards may be achieved outside of these settings. The FDA has indicated that, in some instances, only preclinical or pharmacologic data may be available with very preliminary or no evidence of efficacy. Minimal or absent information on dosing, schedule, or safety would complicate the determination of risk versus benefit in these cases. To insure adequate protection of the patient from undue toxicity and to obtain the best opportunity for clinical benefit, a full array of resources and trained personnel should be available for managing such patients.

The proposed regulations also state that there should be no detrimental effect on recruitment to ongoing clinical trials or to the initiation of such trials. If the expanded-access mechanism were to become popular outside of the recognized oncologic treatment settings, it easily could alter patterns of referral, introduce unintended biases into ongoing clinical studies, or even contribute to disparity. Inequality in access to clinical trials may result if certain individuals are afforded access to experimental drugs without the close clinical or other monitoring that normally is included in clinical trials. If this were to happen, and with the current inadequacies of insurance coverage, some patients may be coerced into carrying the burden of the nontherapeutic components of these studies to obtain a potential benefit. By contrast, other more financially independent patients would be permitted to bypass invasive and perhaps more risk-laden procedures. This may become a larger issue if charging is authorized for investigational drugs on a broader basis than that currently allowed.

Looking at the expanded-access scheme from a different angle, particularly with regard to intermediate groups (10–100 patients), there could be a category of patients who do not meet all of the eligibility criteria for inclusion into research protocols but for whom safety and monitoring for efficacy are the main objectives. This type of expanded access to investigational drugs could be developed either as part of ongoing study protocols or as a separate protocol that provides IND access for rare tumors, as an example. The proposed mechanism would allow submission under a new IND or a protocol amendment to an existing IND, which obviously would require the support of the sponsor.

The expanded IND access goes into effect 30 days after the FDA receives an IND or on earlier notification by the FDA that the expanded access may begin. A probable caveat exists for those patients who have serious life-threatening conditions. Most of these patients would have limited opportunity because of the time involved in the application bureaucracy. This is very relevant for those patients who have only a few months to live.

The FDA has declared in their proposal that, when a significant number of requests for individual patient access are received (for example, 10 requests for the same type of access within 6 months), they may ask the sponsor to submit an IND or protocol for the further use. These would fall under intermediate group or open protocols. The key question is who will be motivated to submit this expanded-access IND application. It probably would be left to the sponsor, assuming they were encouraged to extend the treatment to nonstudy patients or to institutions with the capability to submit the application as sponsor for the number of patients who may be eligible for the expanded-access protocols.

For instances in which studies are in an early phase of development and the sponsor or manufacturer may have limited supplies of an investigational drug, will there be pressure on manufacturers to maintain a drug inventory specifically to support the expanded-access regulation? One possible positive impact of this proposal could be a broadening of eligibility in clinical trials. At the M. D. Anderson Cancer Center, we are seeing this particularly in new protocols that involve the leukemias and lymphomas, in which eligibility is expanded to include a variety of patient subsets, usually with common molecular features, and is justified statistically.

A stated objective of these new regulations is that the proposed rule would “ease the administrative burdens of physicians seeking investigational drugs for their patients and on sponsors who are willing to make promising, unapproved therapies available for treatment use.” It certainly is possible that institutions that treat large numbers of patients who ordinarily are candidates for clinical trials or who have uncommon or rare cancers may welcome the expanded access, particularly for the intermediate group. The larger question is whether Pharma will show greater willingness to provide investigational drugs for these studies. In view of the number of individuals and hours involved in these applications, intermediate-group access protocols certainly would be preferred to the individual patient study.

The FDA has stated that there would be “private benefits to individual patients who receive the drug and social benefits if the private benefits were also valued by society.” The FDA also is aware of the potential adverse consequences of making investigational drugs available prematurely and has stated that the authorization process would be contingent upon some evidence of drug safety and effectiveness, although this may not always be the case, particularly with individual-access applications. To determine a societal benefit, it is also important that data from the expanded-access protocols be analyzed and published. This could be done more easily in the intermediate and open-access groups, for which the protocol and informed-consent documents could address the issue appropriately. INDs for individual access also could be composed to allow for subsequent data collection under the retrospective chart review. Review of the application, development of an appropriate informed-consent document, and provision of an adequate monitoring plan will require added time for an executive IRB review. The FDA hasestimated that it will take 8 hours to prepare individual IND applications. For the intermediate expanded-access patient population, the FDA has estimated that the requirement will be for 120 hours of staff time divided between the Director of Clinical Research, typically a medical doctor (approximately 50% or 60 hours); a Director of Regulatory Affairs (approximately 20% or 24 hours); and a Clinical Research Associate (approximately 30% or 36 hours). If the process becomes frequent, then additional personnel and costs will need to be taken into consideration. The FDA has offered an approximate cost of preparing and submitting an intermediate-population, expanded-access request of $11,100 and has commented that consolidation by transitioning from multiple, individual patient-expanded INDs to a single IND or to a protocol for intermediate patient groups should reduce the administrative burden for sponsors. This estimate does not fully cover the initial and continuing IRB review or the added monitoring that would be required. It also will be important to consider its impact on hospital and institutional regulatory departments, which already may be overwhelmed by multiagency regulations. In addition, it raises the question of whether individuals in practice at small community hospitals would have 1) sufficient expertise and resources to process these applications and 2) access to an environment that assures adequate safety monitoring during treatment and follow-up.

New proposed IND regulations, which have been published in the Federal Register (2006N-0061), also clarify the criteria for charging patients for investigational drugs through expanded access. These regulations describe the criteria required to support an application by a sponsor to charge for the direct costs of an investigational drug. The sponsor may apply for charging authorization in all 3 expanded-access categories. To insure that patient disparity issues are addressed and that vulnerable and underserved patients are included in the process so that they also may obtain the potential benefits of experimental drugs, it is necessary that Medicare/Medicaid regulations be placed in harmony with the expanded-access plan.

The FDA's new proposals for expanded access and for charging for INDs potentially may benefit certain cancer patients and the community. However, key issues that warrant attention include 1) how the purpose of promoting broader access can be achieved fairly while promoting the best possible outcomes for a majority of patients eligible for treatment under the new regulations; 2) insuring that authorization for investigational drugs is covered transparently in federal, state, and privately supported insurance programs; 3) insuring that good medical practice principles apply, the new regulations should clarify that there can be no substitute for experience or training and the availability of resources in the use of the investigational drugs in patients; and 4) providing a seamless process that will encourage manufacturers, sponsors, and physicians to participate more actively in the expanded-access program.

Notwithstanding legal issues concerning a patient's right to access investigational drugs, overall, the proposed regulations that will replace the current regulations on expanded access represent a move in the right direction. The revised regulations also provide an opportunity to obtain greater clarity in the existing processes for obtaining expanded access to investigational drugs.

REFERENCES

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  2. REFERENCES
  • 1
    Department of Health and Human Services, Food and Drug Administration. Expanded access to investigational drugs for treatment use. Docket no. 2006N-0062. Fed Reg. 2006; 71: 7514775168.
  • 2
    Department of Health and Human Services, Food and Drug Administration. Charging for investigational drugs. Docket no. 2006N-0061. Fed Reg. 2006; 71: 7516875181.