Background Clinical Trials When patients are seeking access to investigational drugs, their first option is to consider whether they can obtain them through participation in a clinical trial. Clinical trials are a step in the drug development process through which a drug manufacturer assesses the safety and effectiveness of its investigational drug through human testing. A clinical trial can take place in a variety of settings (e.g., research hospitals, universities, and community clinics) and geographic locations, and is led by a principal investigator that is typically a physician. Manufacturers establish clinical trial eligibility criteria to define the patient population to be studied, and only patients who meet those criteria can participate. These criteria can vary depending on the drug being studied and its intended use. Patient eligibility criteria consist of both inclusion and exclusion criteria. Inclusion criteria specify the characteristics of the patient that are required for participation, such as the stage or characteristics of a disease, and typically identify a patient population in which it is expected that the manufacturer can demonstrate the effect of an investigational drug. In comparison, exclusion criteria specify the characteristics that disqualify patients from clinical trial participation and can include factors that could mask the effect of an investigational drug, such as the presence of comorbidities or simultaneous use of other drugs. Certain patient populations, such as children and pregnant women, may also be excluded from clinical trial participation because of ethical reasons. Drug manufacturers, FDA, and IRBs each have responsibilities as part of the clinical trial process. In order to test an investigational drug on human volunteers in clinical trials, a manufacturer must first submit an investigational new drug application (IND) to FDA. FDA is responsible for reviewing the IND, which includes various components such as the clinical trial protocol that describes the patient eligibility criteria, the medications and dosages to be studied, and other details. In turn, an IRB is responsible for reviewing and approving the clinical trial protocol as well as reviewing the informed consent form for the study. In general, clinical trials that involve human volunteers can begin after FDA has reviewed and allowed the IND to proceed and the IRB has given its approval. An investigational drug typically goes through three phases of clinical trials before an application is submitted to FDA for marketing approval. At any point during the clinical trials, FDA could issue a clinical hold on the existing IND that would delay the proposed clinical trials or suspend the ongoing clinical trials. When a proposed or ongoing study is placed on a complete clinical hold, the investigational drug cannot be administered to any human volunteers. Traditionally, the three clinical trial phases are the following: Phase I: This clinical trial phase generally tests the safety of the drug on about 20 to 80 healthy volunteers. The goal of this phase is to determine the drug’s most frequent side effects and how it is metabolized and excreted. If the drug does not show unacceptable toxicity in the phase I clinical trials, it may move on to phase II. Phase II: This clinical trial phase assesses the drug’s safety and effectiveness on people who have a certain disease or condition, and typically the assessment is conducted on a few dozen to hundreds of volunteers. Generally, during this phase some volunteers receive the drug and others receive a control, such as a placebo. If there is evidence that the drug is effective in the phase II clinical trials, it may move on to phase III. Phase III: This clinical trial phase generally involves several hundreds to thousands of volunteers who have a certain disease or condition and gathers more information about the drug’s safety and effectiveness, again while being compared to a control. If phase III clinical trials are successfully completed, the drug may move on to FDA’s review and approval process. When seeking FDA’s approval to market a drug in the United States, the manufacturer submits an application to FDA that includes the data from the safety and efficacy clinical trials for FDA to review. Safety data include clinical trial results about a drug’s toxicity (e.g., the highest tolerable dose) and adverse events that may result from exposure to the drug. Efficacy data include information on whether the drug demonstrated a health benefit over a placebo. FDA reviews the information in the application to either approve or not approve the drug. FDA’s Expanded Access Program If a patient seeking access to an investigational drug is not able to participate in the drug’s clinical trial (e.g., because of the study’s eligibility criteria or geographic location), another pathway to potentially obtain access to the drug outside of a clinical trial is through FDA’s expanded access program. Under the program, a licensed physician can submit a request for access to an investigational drug for treatment use on behalf of a patient and may do so during or after phase I, II, or III of clinical trials. To allow access to an investigational drug under the program, FDA must determine that a patient has a serious or immediately life-threatening disease or condition and has no other comparable medical options, among other criteria. FDA’s goals for the program are to facilitate the availability of investigational drugs when appropriate, ensure patient safety, and preserve the clinical trial development process. FDA is responsible for determining whether to allow individual requests to proceed to treatment once the manufacturer has agreed to provide access. If FDA allows the request to proceed, an IRB must approve the clinical treatment plan that is submitted as part of the individual request and review the informed consent form. The licensed physician treating a patient under expanded access would be required to report to FDA any unexpected serious adverse reactions that occur during treatment for which there is a reasonable possibility that the drug caused the reaction. The Federal RTT Act In 2018 the federal RTT Act established another pathway through which patients may potentially obtain access to investigational drugs outside of clinical trials. To be eligible under the law, a patient must have been diagnosed with a life-threatening disease or condition, have exhausted approved treatment options, and be unable to participate in a clinical trial involving the investigational drug. Obtaining access to investigational drugs through the federal RTT Act primarily requires the involvement of the manufacturer and treating physician. Similar to FDA’s expanded access program, treatment can only proceed if the drug manufacturer allows the patient access to its drug. Under the federal RTT Act, the manufacturer is responsible for providing to FDA an annual summary of any use of its drugs under this pathway that includes information on any known serious adverse events. The treating physician is responsible for requesting access to the investigational drug for the patient and for obtaining written informed consent from or on behalf of the patient if the manufacturer agrees to provide access. Eligibility of an investigational drug for patient use through this pathway is based on certain criteria, including that the drug has completed phase I clinical trials, the manufacturer has not discontinued clinical development of the drug, and the drug has not been placed on a clinical hold. Unlike FDA’s expanded access program, the federal RTT Act does not require the FDA or an IRB to review individual requests for access. Figure 1 shows a summary of the three pathways through which patients may obtain access to investigational drugs. FDA Issued Guidance to Help Manufacturers Broaden Clinical Trial Eligibility Criteria and Two Manufacturers We Interviewed Took Steps to Broaden Their Criteria Some patients, such as those with compromised liver and kidney function, have traditionally been excluded from clinical trials. FDA has ongoing efforts to help drug manufacturers identify the circumstances under which they could broaden their eligibility criteria to include such patients without compromising study results. These efforts include issuing recent guidance with recommendations for including certain patients in clinical trials for cancer drugs. Officials from one of the 10 drug manufacturers we interviewed told us they had broadened their eligibility criteria and another one was taking steps to do so, but these officials and others noted challenges to broadening eligibility criteria. FDA public workshop on broadening eligibility criteria. In April 2018, FDA held a public workshop with stakeholders—including drug manufacturers, patient advocacy groups, and government agencies—to discuss ways drug manufacturers and other investigators could safely broaden eligibility criteria for clinical trials and to inform FDA guidance on this topic. In July 2018 FDA publicly released a report summarizing the workshop, in accordance with FDARA. According to the report, stakeholders at the meeting emphasized the importance of broadening clinical trial eligibility, when appropriate, to include more patients who will likely use the drug if it is approved. Stakeholders recommended that investigators ensure that the eligibility criteria for each of their clinical trials are scientifically justifiable, rather than, for example, “copying and pasting” a narrow set of criteria from a prior study without considering if the exclusions are valid for scientific reasons. According to the report, this practice can unnecessarily limit eligibility for certain patients. While stakeholders commented that assessing whether eligibility criteria are scientifically justifiable may require additional time and resources, they emphasized it could lead to the removal of unnecessarily restrictive eligibility criteria and thereby increase participation among patient populations that have been typically excluded from clinical trials, such as pediatric patients and patients with compromised liver and kidney function. FDA guidance on eligibility criteria. In March 2019, FDA issued four new draft guidance documents and finalized one guidance document with recommendations for drug manufacturers to broaden clinical trial eligibility criteria for drugs that treat cancer. The guidance recommends that manufacturers include certain patient populations that have typically been excluded from participation. The patient populations are adolescents; pediatrics (children and adolescents); patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infections; patients with brain metastases (i.e., cancer that has spread to the brain); and patients with compromised kidney, heart, or liver function, or who have a history of (or concurrent) cancer. According to FDA, the guidance documents are intended to help drug manufacturers and other investigators broaden cancer trial eligibility criteria. This will help improve patient access to investigational drugs and ensure that the results from the clinical trials are generalizable to patients likely to use the drugs once they are approved. In addition, FDA officials have noted that including broader patient populations in clinical trials can lead to new information in a drug’s labeling, which will help communicate the safe and effective use of these drugs. Table 1 provides a summary of each of the five guidance documents. In June 2019, FDA issued draft guidance for manufacturers on broadening clinical trial eligibility criteria, in accordance with FDARA. The guidance applies to a wider range of clinical trials beyond cancer trials and includes recommendations to broaden eligibility criteria and considerations for the use of clinical trial designs and other methodologies to help facilitate patient participation. For example, FDA recommends that manufacturers examine each exclusion criterion to determine if it is needed to help assure the safety of trial participants or to achieve the study’s objectives. If not, the manufacturer should consider eliminating or modifying the criterion to expand the study population as well as tailoring the exclusion criteria as narrowly as possible to avoid unnecessary restrictions to the study population. Two manufacturers’ efforts to broaden eligibility criteria. Officials from one of the 10 drug manufacturers we interviewed told us they broadened their clinical trial eligibility criteria and another manufacturer we interviewed reported that it was taking steps to do so. These two manufacturers told us they were taking these steps in part because both believe it will facilitate the drug approval process. Officials from one manufacturer stated that they broadened their eligibility criteria by removing exclusions after determining they were not critical to clinical trial designs, including exclusions related to liver function, infections (e.g., HIV), and the use of other medications (e.g., steroids). The officials explained that, since 2015, they have systematically evaluated their eligibility criteria to ensure that they do not unnecessarily exclude patient populations from their clinical trials. Officials from the second manufacturer told us they have begun evaluating whether to remove certain exclusion criteria that they typically use in clinical trials, and added that their efforts are partially in response to FDA’s 2018 public workshop report, as described above. For example, the manufacturer is reviewing its exclusion of adolescents in prior clinical trials and officials told us they will likely include adolescents in an upcoming study if they determine that patient safety would not be compromised. Officials from both manufacturers stated that broader eligibility criteria will allow more patients to access investigational drugs through clinical trial participation. It can also, officials said, help them obtain FDA approval for a drug that extends to a wider range of patients, if the drug is found to be safe and effective. Further, officials from one of the two manufacturers noted that broader eligibility criteria, such as criteria that include patients with infections, could help streamline the process for conducting clinical trials—for example, by eliminating the need to conduct clinical testing to screen for the presence of infections. Although most drug manufacturers in our review did not report efforts to broaden their eligibility criteria, many noted efforts to address other barriers to clinical trial participation. For example, to address geographic barriers, officials from six of the 10 manufacturers told us they help cover costs for patients to travel to clinical trial sites, such as by reimbursing transportation and hotel costs for patients who travel long distances. In addition, officials from one manufacturer said they completed a pilot clinical trial on diabetes in 2019 that used decentralized trial locations in three states, such as retail health clinics and patients’ homes, to help patients overcome challenges with obtaining transportation to trial sites. Similarly, within the next 2 years, another manufacturer is planning to conduct a pilot clinical trial that is fully remote and expects the design to improve patient participation in rural communities. To address the lack of information about upcoming and ongoing clinical trials that is available to and tailored to patients, two manufacturers launched clinical trial registries in 2015 and 2016, respectively. Officials from one of the manufacturers stated they designed their registry to bridge the gap between the information that patients want about clinical trials (e.g., information targeted to medical conditions that uses basic terminology), and what is available in ClinicalTrials.gov, a federal database that includes information on privately and publicly funded clinical trial studies. Officials explained that ClinicalTrials.gov is, in general, more targeted to physicians. In addition, to address barriers associated with the mistrust of research stemming from historical events among African-Americans and other communities, one manufacturer has several ongoing efforts to increase the participation of racially and ethnically diverse populations in its clinical trials. For example, the manufacturer conducts workshops to train minority investigators who conduct clinical trials and requires certain clinical trial sites to be located in areas with minority patient populations of more than 25 percent. Challenges with broadening eligibility criteria. Officials from four of the 10 drug manufacturers we interviewed—including the two taking steps to broaden their clinical trial eligibility criteria—told us broadening eligibility criteria is challenging. They stated that broader criteria must be carefully balanced with the need to collect evidence from a well-defined population. Officials from one manufacturer explained that removing standard exclusion criteria, such as excluding patients who use other medications, could interfere with the success of their clinical trial if those medications make it difficult to identify the effects of the studied drug. In addition, officials from another manufacturer emphasized that determining whether to remove exclusion criteria takes time and resources because it involves additional study, which could slow down the clinical development of a drug. FDA Took Several Recent Actions to Facilitate Access to Investigational Drugs Outside of Clinical Trials FDA Simplified the Institutional Review Board Process and Launched a Pilot Program to Facilitate Access to Investigational Drugs Outside of Clinical Trials To facilitate access to investigational drugs outside of clinical trials, FDA has simplified its expanded access program’s IRB review requirements for individual patient requests. FDA made this change in October 2017, in accordance with a provision in FDARA. This provision addressed concerns that FDA’s requirement to convene a full IRB to review an expanded access request could result in delays of approvals because full IRBs may not meet regularly. Under the revised process, FDA now allows for a waiver of the requirement for full IRB review when concurrence is obtained by the IRB chair or another designated member. According to FDA officials, the updated process will help reduce the potential burden for physicians, who are responsible for obtaining IRB approval, while still protecting patients. In addition, to further simplify its expanded access process for individual patient requests, in June 2019 FDA launched a pilot program called Project Facilitate for oncologists and other health care professionals that treat patients with cancer. According to FDA officials, the pilot program is focused on oncology because the agency receives a large number of individual expanded access requests from oncologists. Under the pilot program, FDA established a new call center that provides a single point of contact where FDA staff are available to answer questions, assist in filling out appropriate paperwork, and facilitate the overall process for requesting and obtaining access to investigational drugs. For example, FDA officials told us that FDA staff may assist oncologists in locating an IRB, if needed. As part of the pilot program, FDA will follow up on individual requests and gather data, such as how many patients received investigational drugs, and if not, why the requests were denied by manufacturers. According to FDA, the agency can use these data to determine how the process is benefiting patients. Twenty of the stakeholders we interviewed were familiar with FDA’s simplified IRB review requirements, and of those, 18 told us these updates were helpful for physicians and patients. For example, officials from one drug manufacturer commented that the new IRB review requirements reduce the amount of time it takes for patients to obtain access to investigational drugs, which is especially important for patients who are very sick. In addition, we spoke to 12 stakeholders about FDA’s plans for its pilot program, and of those, nine generally had positive views of the agency’s planned activities. Officials from one manufacturer explained that the pilot program could help reduce the burden on oncologists seeking access to investigational drugs for their patients through the expanded access program. On the other hand, the officials from this same manufacturer raised concerns about the potential for FDA to intentionally or unintentionally pressure companies to make their investigational drugs available to patients, should FDA have increased involvement with drug manufacturers as part of the pilot program. FDA Increased Communication about the Expanded Access Program and the Federal RTT Act to Facilitate Access to Investigational Drugs Outside of Clinical Trials FDA has also taken recent actions to facilitate access to investigational drugs outside of clinical trials by increasing its communication about the expanded access program and the federal RTT Act. FDA’s increased communication about the expanded access program. In November 2018, FDA updated the web pages for its expanded access program in response to findings from an external assessment that the web pages were difficult to navigate and contained unclear information. FDA created separate web pages for patients, physicians, and drug manufacturers, and tailored information about the expanded access process to each of these stakeholders. In addition, FDA added a new web page with information that is commonly requested by physicians and patients, such as the instructions for completing the form for submitting individual requests and definitions of keywords associated with the expanded access process (e.g., IRB, informed consent). In addition, in October 2017, in response to a recommendation in our July 2017 report, FDA clarified its guidance for drug manufacturers on how the agency reviews adverse events that occur under FDA’s expanded access program. In the 2017 report, we found that some drug manufacturers were concerned that use of adverse event data may influence FDA in making final approval decisions, and that this possibility could contribute to a manufacturer deciding not to grant patients access to their drugs through the expanded access program. In response, we recommended that FDA clearly communicate how the agency will use adverse event data from expanded access use when reviewing drugs and biologics for approval. FDA’s updated guidance states that FDA is not aware of instances in which adverse event information prevented the agency from approving a drug, and that it is very rare for FDA to place a clinical hold on an investigational drug due to adverse events observed during expanded access treatment. The guidance also explains that several factors make it difficult for FDA to link an adverse event to the expanded use of a drug being considered for approval. For example, the guidance acknowledges that the use of investigational drugs though the expanded access program generally occurs outside of a controlled clinical trial setting and patients receiving such drugs may be sicker than patients participating in a clinical trial, making it more difficult to determine whether the use of the investigational drug has led to the adverse event. In responding to questions about increased FDA communication about the expanded access program, 19 of the stakeholders we interviewed were familiar with FDA’s updated expanded access web pages, and of those, 16 told us they were an improvement. Officials from one physician organization stated that the updated web pages were easier to navigate than the previous web pages and presented information about the process more clearly. Among the 10 manufacturers we interviewed, we found varying views of FDA’s updated guidance on the use of adverse event data. Officials from seven of the 10 manufacturers viewed the updated guidance as an improvement. Officials from one of the seven explained that it contributed to their company’s decision to allow access to investigational drugs, when appropriate. Officials from two of the 10 manufacturers did not view the guidance as an improvement. Officials from both manufacturers stated that they still had significant concerns about the potential use of adverse event data by FDA to adversely affect the development of their investigational drugs, such as being used to issue a clinical hold. An official from one of the two manufacturers commented that these concerns remained despite FDA’s statement in the guidance that it is difficult for FDA to link expanded access use to a particular adverse event. In addition, officials from two other manufacturers who viewed the guidance as an improvement similarly expressed remaining concerns that adverse events could negatively affect the development of their investigational drugs. One manufacturer was unfamiliar with the updated guidance. Further, officials from four of the 10 drug manufacturers we interviewed, including two who viewed the updated guidance as an improvement, said they believed that manufacturers’ concerns about this issue may never be fully resolved even with additional FDA guidance. In other comments related to FDA’s communication on its use of adverse events data from the expanded access program, some drug manufacturers we interviewed noted the merits of using efficacy and safety data from the expanded access program to inform FDA’s drug approval decisions. Officials from two of the 10 manufacturers told us they believe that FDA’s potential use of adverse event data from expanded access use, but not efficacy data, would be unfair. Officials from one of these two manufacturers cited FDA’s updated guidance on adverse events as contributing to their view, referring to FDA’s statement that it is unlikely that FDA’s program would yield data that is useful to FDA in considering an investigational drug’s effectiveness. However, FDA officials told us that efficacy and safety data from the expanded access program have been used to support drug approvals in several instances. For example, in January 2018 FDA approved the drug Lutathera to treat rare tumors in the pancreas and gastrointestinal tract using efficacy and safety data the manufacturer submitted to FDA from a subset of the roughly 1,200 patients who received the drug through the expanded access program. Officials from four of the 10 manufacturers expressed interest in discussing further with FDA how the agency would evaluate efficacy and safety data from the expanded access program and use these data to help support a drug’s approval and other regulatory decisions. FDA’s communication about the federal RTT Act. In November 2018, FDA launched a new federal RTT web page that outlines both the eligibility requirements for patients interested in seeking access to investigational drugs and the criteria that must be met for an investigational drug to be eligible for use through this pathway. For example, the web page states that patients must be diagnosed with a life- threatening disease or condition to be eligible to access investigational drugs under the federal RTT pathway. Further, the agency plans to issue proposed regulations in September 2019 to implement the federal RTT Act requirement for manufacturers to submit an annual summary to FDA on any use of their investigational drugs under this pathway. The regulations will include a due date for manufacturers to submit the annual summaries as well as information on what they are to contain, according to FDA. Fourteen of the stakeholders we interviewed were familiar with FDA’s new web page on the federal RTT Act, and among those, eight stated that it communicated useful and balanced information for physicians and patients. Officials from the remaining six stakeholders told us they did not find it helpful for physicians or patients. For example, officials from two stakeholders (including one drug manufacturer) commented at the time of our review that the web page could be misleading to some patients if they interpret the federal RTT Act to mean that manufacturers must provide access to their investigational drugs. Both added that FDA should more clearly communicate on the web page that there is no such requirement. In addition, officials from another stakeholder stated at the time of our review that FDA should explain on the web page the agency’s role in implementing the federal RTT Act. In May 2019 FDA clarified on its web page that the federal RTT Act does not require manufacturers to provide patients access to their investigational drugs and that FDA’s role includes posting a consolidated annual summary report on the use of investigational drugs through the federal RTT pathway. Most Selected Manufacturers Communicated Whether They Consider Requests for Access to Investigational Drugs Outside of Clinical Trials and Conditions for Approval Most of the 29 drug manufacturers in our review used their websites to communicate to patients and physicians whether they would consider individual requests for access to their investigational drugs outside of clinical trials. Among those that would consider requests, most also communicated the conditions under which they would review requests and grant access. Manufacturers’ consideration of requests for access. Our review of drug manufacturers’ websites between January 31, 2019, and March 12, 2019, found that 23 of the 29 manufacturers in our review used their websites to communicate whether they considered individual requests for access to investigational drugs outside of clinical trials. In communicating this information, 19 of the 23 manufacturers stated they were willing to consider requests, while the other four stated they were not considering requests. The remaining six of the 29 manufacturers did not communicate information about whether they would consider requests for access to investigational drugs outside of clinical trials at the time of our review, but officials from all six told us they were in the process of developing content on this topic that they intended to post on their websites. Information communicated by manufacturers that consider requests. Among the 19 manufacturers willing to consider requests for access to investigational drugs outside of clinical trials, all communicated on their websites that they required physicians to submit requests on behalf of their patients and provided information on how physicians should submit these requests. In addition, 18 manufacturers communicated an estimated time frame within which they would respond to requests. The manufacturers provided additional information, including the following: Eighteen communicated information about the type of patient for whom they would consider granting access. Eighteen stated that patients must have a serious or life- threatening disease or condition; have no comparable or satisfactory alternative therapies available; and be unable to participate in a clinical trial to be eligible to obtain access. In addition, 17 stated that the treating physician must determine for the patient seeking access that the risk of taking the investigational drug is not greater than the anticipated benefit. Fifteen communicated other factors they would take into account during their review of requests. These factors included the following: Ten stated that the supply of their investigational drugs was a consideration. That is, a manufacturer must have a sufficient supply of the investigational drug to support the drug’s clinical development before granting access to patients outside of clinical trials. Five referred to specific drugs to which they would consider granting access when describing the conditions under which they would consider reviewing requests. For example, one manufacturer stated that it would consider requests to access three of its investigational drugs (intended to treat bladder cancer, influenza, and HIV). One manufacturer communicated that after its initial review of individual requests, it uses an external advisory committee to further evaluate certain requests and ensure they are evaluated in an ethical and fair manner. The committee, which includes bioethical experts, physicians and patient representatives, makes recommendations to the manufacturer about providing access to individual patients. Many of the 19 manufacturers that communicated they were willing to consider individual requests for access stated that after they have approved a request they also required external entities to review the request. These included the following: Thirteen stated they require the relevant regulatory authority to review requests. Of these, six specified that they require FDA to review requests for access in the United States. One of these six explained that it required a review by FDA to ensure all available safety data for the investigational drug were considered, and added that FDA is uniquely aware of such safety data. Five stated they require the review of a research ethics committee or an IRB. Information communicated by manufacturers that do not consider requests. Among the four manufacturers that communicated on their websites they were not considering requests for access to investigational drugs outside of clinical trials at the time of our review, two provided reasons for their decision. Both cited safety concerns; for example, one explained that it wanted to ensure its investigational drugs were administered to patients only through clinical trials where safety could be closely monitored. One also cited limited resources, stating that it chose to focus its resources solely on conducting clinical trials. Both of the manufacturers that provided reasons for not considering requests for access communicated that they will periodically re-evaluate their policies. Agency Comments We provided a draft of this report to HHS for comment and HHS provided technical comments, which we incorporated as appropriate. We are sending copies of this report to the appropriate congressional committees, the Secretary of the Department of Health and Human Services, and other interested parties. In addition, the report is available at no charge on the GAO website at http://www.gao.gov. If you or your staff have any questions about this report, please contact me at (202) 512-7114 or dickenj@gao.gov. Contact points for Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made key contributions to this report are listed in appendix I. Appendix I: GAO Contact and Staff Acknowledgments GAO Contact Staff Acknowledgments John E. Dicken at (202) 512-7114 or dickenj@gao.gov In addition to the contact named above, Gerardine Brennan, Assistant Director; Pamela Dooley, Analyst-in-Charge; Craig Gertsch; Gay Hee Lee; and Moira Lenox made key contributions to this report. Also contributing were George Bogart, Laurie Pachter, and Ethiene Salgado- Rodriguez.