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 Complaint and Request for Investigation February 21, 2002 USDA/APHIS/AC Dear Sir or Madam: On behalf of the Physicians Committee for Responsible Medicine (PCRM) and its more than 100,000 members, this letter shall serve as a formal complaint and request for a USDA investigation regarding experiments proposed and conducted by Ohio State University (OSU) veterinarian Michael Podell in protocol No. 00A0066, "A Feline Model of NeuroAIDS and Drug Abuse," pursuant to Section 13(a)(3)(B) of the Animal Welfare Act; Title 9 of the Code of Federal Regulations; Policy #12 (Consideration of Alternatives to Painful/Distressful Procedures) of the USDA Animal and Plant Health Inspection Animal Care Policy Manual; U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training; and the Public Health Service Policy on Humane Care and Use of Laboratory Animals. Evidence indicates that Dr. Podell provided irrelevant and insufficient information regarding his purported consideration of "alternatives" to animal use in both his Institutional Laboratory Animal Care and Use Committee (ILACUC) Animal Use Protocol Questionnaire, submitted by Dr. Podell for approval of his proposed experiment, and in his National Institutes of Health (NIH) grant application. Copies of Dr. Podell's completed ILACUC questionnaire and NIH grant application are enclosed herein. Further evidence indicates that the OSU ILACUC is noncompliant with these various federal policies mandating that it require researchers to search for alternatives to the use of animals as a condition for approving a proposed protocol. In particular, its procedures are inadequate to ensure that investigators have appropriately considered alternatives to proposed animal experiments, and it approved a protocol submitted by Dr. Podell that indicated an inadequate search for alternatives. A separate complaint letter was sent by PCRM to the OSU ILACUC and the National Institute on Drug Abuse (NIDA) regarding the same concerns raised herein. Background Dr. Podell's research proposal was submitted in response to a Request for Applications (RFA) issued by NIDA regarding interactions between drug use and Human Immunodeficiency Virus (HIV). The main goal of the RFA was the development of research to understand the relationship between drug abuse and addiction, impulsive and risk-taking behaviors (such as needle-sharing and unprotected sexual encounters), and decision-making processes that can lead to contracting HIV (such as whether the disinhibition caused by drug abuse may also encourage unsafe sexual practices). Another research interest set forth in the RFA was the interaction between drug abuse and HIV, specifically their abilities to cause neurological damage, both separately and in combination. Methamphetamine, also known as "speed," can lead to neurological sequelae that have been under active study in humans. Likewise, HIV causes brain pathology, which has also been extensively studied in human patients. The combined neurological effects of amphetamine use and HIV have been the subject of human research, particularly in HIV-positive individuals using methamphetamine illicitly or receiving amphetamines in treatment programs and in clinical trials. Nevertheless, in his ILACUC questionnaire and in his NIH grant application, Dr. Podell proposed a crude model for the combined effects of methamphetamine and HIV. Rather than study human patients or viruses capable of causing human illness, he proposed to administer methamphetamine to cats and to infect them with Feline Immunodeficiency Virus (FIV). Dr. Podell requested $1,150,000 in direct costs and authorization to use l08 cats and the drug methamphetamine. He was reportedly awarded $1.68 million in a five-year grant. Inadequate Search for Alternatives Because his proposed experiments are invasive, stressful (involving the administration of psychotropic drugs, an infectious illness, and a variety of test procedures), and ultimately fatal, Dr. Podell was required to apply to the OSU ILACUC for approval by completing the animal use protocol questionnaire. In doing so, federal law requires that he search for alternatives to the proposed experiments and that the ILACUC confirm an adequate search before approving any protocol. However, in his completed ILACUC questionnaire, Dr. Podell merely indicated how he searched for duplication, not for alternatives, as will be described below, and thus failed to conduct an adequate search for alternatives. As such, the ILACUC failed to enforce federal law requiring an investigator to search for alternatives to the use of animals as a condition for approving a proposed protocol. The search for alternative methods is an essential provision of APHIS policy. According to APHIS Policy #12 of the Animal Care Resource Guide, "Alternatives or alternative methods are generally regarded as those that incorporate some aspect of replacement, reduction, or refinement of animal use in pursuit of the minimization of animal pain and distress consistent with the goals of the research." Such alternatives include, although are not limited to, the use of other species—including human (clinical) research—that may serve the same research purposes. Moreover, APHIS provides guidance on the procedures to be used in searching for the best alternatives, explicitly stating that computerized searches are not to be the sole means for seeking alternatives in specialized fields of study. In particular, according to APHIS Policy #12, a database search remains the most effective and efficient means of considering alternatives, but "in some circumstances (as in highly specialized fields of study), conferences, colloquia, subject expert consultants, or other sources may provide relevant and up-to-date information regarding alternatives in lieu of, or in addition to, a database search." Database searches are often inadequate because, first, they do not retrieve current or unpublished research studies and, second, they are limited by the choice of search terms. A search limited to a specific species, such as cats, for example, is unlikely to retrieve published reports on similar research in humans. The search for alternatives must be conducted in the context of the overall research goals. Dr. Podell stated his goal on page 2 of his NIH grant application: "The goal is to elucidate on [sic] the effects and mechanisms of METH and HIV-1 interaction." In other words, the primary expressed intent was to advance the understanding of the human pathological condition, not to characterize interactions between the feline virus FIV and drug use or to find means of treating FIV. Even before reviewing his account of his search for alternatives, readers of Dr. Podell's NIH grant application have reason for concern regarding his thoroughness and attention to detail. On page 4 of the application, entitled "Budjet [sic] Justification Page," his total direct costs are rounded off, and his sum of total costs is incorrect by a factor of one thousand. In his ILACUC questionnaire, Dr. Podell indicated that he had searched for alternatives to procedures in his experiment that might cause more than momentary or slight pain or distress, and had found none. In actuality, however, in his search for "alternatives," Dr. Podell relied on a narrow, perfunctory, and poorly planned computerized search designed to identify duplication, not alternatives. That is, he sought published experiments that essentially duplicated the techniques he was planning to use, rather than seeking alternative methods that could address the overall research goals more humanely or effectively. Dr. Podell's search for alternatives was conducted as follows, according to page 5 of his ILACUC application: He consulted two databases, Medline and Toxline, using only four keywords: "feline," "methamphetamine," "FIV," and "neuroAIDS." There is no evidence that he looked for any published studies coded with the words "HIV," "Acquired Immunodeficiency Syndrome," or "amphetamine"; nor is there evidence that he sought alternatives using the other methods recommended by APHIS. We question whether Dr. Podell actually conducted a knowledgeable search using the keyword "NeuroAIDS," as the MeSH Browser function of PubMed informs users that this term is not a listed medical subject heading. This fact does not prevent an investigator from conducting a search, but it suggests that a search is likely to be unproductive and guides the user to other terms. A search of the term "NeuroAIDS" on February 20, 2002, yielded only 20 references. FIV is also not a listed medical subject heading, although "immunodeficiency virus, feline" is, and searches using either the terms "FIV" or "immunodeficiency virus, feline" produce some references. However, it is inappropriate to limit the search by using the terms "feline" and "FIV." Such terms would tend to exclude lines of inquiry other than the model Dr. Podell preferred. APHIS procedures call for a search for research methods using species other than the one initially under consideration, but we find no evidence that Dr. Podell complied with this mandate. A Medline search run on February 20, 2002, using the keyword "FIV" yielded 991 references. In contrast, a search using "HIV" produced 109,876 references. Focusing the search is, of course, necessary, but doing so in such a way as to exclude HIV-related references would tend to badly skew the results and eliminate most relevant studies. Also, by limiting his search to "methamphetamine," Dr. Podell excluded studies using other forms of amphetamine that may have similar brain effects. A search using the keyword "methamphetamine" yielded 3,765 references, while a search using the term "amphetamine" produced 16,479 references. Dr. Podell's failure to search for alternatives and, instead, search for duplication is fostered by the ILACUC questionnaire, which simply asks researchers to confirm that they have "considered alternatives to procedures that might cause more than momentary or slight pain" and "not found such alternatives." It continues by asking researchers to indicate—via a check-the-box approach—which database(s) were searched and the keywords used, to identify any other type of search performed, the years covered by the search, and the date of the search. This brief checklist allows researchers to search for previous experiments using essentially the same method (duplication) and evade the separate and more detailed requirement of searching for methods that advance the research goals by different means (alternatives). Dr. Podell reported that he had searched for alternatives when he had, in fact, only searched for duplication. It is likely that the approach used by the OSU ILACUC will rarely, if ever, elucidate information showing an adequate search for alternatives. In this regard, OSU is not alone. An April 2000 APHIS report titled "USDA Employee Survey on the Effectiveness of IACUC Regulations" examined the effectiveness of the USDA's current approach to ensuring the humane care and use of animals at research facilities through the use of institutional animal care and use committees. (See http://www.aphis.gov/ac/iacucaugust. pdf; accessed February 2002.) The report stated that the "search for alternatives" was the "most frequently cited problem area" for ensuring the humane treatment of animals, and that "review of painful procedures" was the "next most frequently cited problem." In order to assess whether investigators have performed an adequate search for alternatives, the OSU ILACUC must revise its questionnaire. In so doing, it should make it clear that research methods selected should be applied to human medical needs and that human studies are preferred unless there is a compelling ethical or practical reason why such studies cannot be done. Searches for related studies should not be limited as to species, and a search mechanism for current or unpublished studies must be included. The questionnaire should request a thorough explanation of the search method and rationale, including, for example, which databases were selected and why, the rationale for the choice of keywords, and the search results. Computerized searches alone should generally not be considered adequate, and other search methods should also be described. Investigators must make a clear and convincing case favoring the chosen method in light of the overall study goals and available methods. The questionnaire should specify that the investigator has searched for alternative research methods not only for the overall project, but also for each specific procedure that may cause pain or distress. Finally, the ILACUC must meaningfully assess whether the researcher has performed an adequate search and satisfactorily justified any conclusion that no alternatives were available. Better Available Research Methods All research methods have advantages and disadvantages. Animal models offer the advantage that the experimenter can be more invasive with the subjects' anatomy, behavior, and environment, and can kill the subjects for pathological study at any time. However, animal models also have considerable disadvantages. They exclude the possibility of studying subtle brain effects, such as receptive and expressive language deficits, mood alterations, delusions, hallucinations, and mild dementia. They also include the complicating factors of major species differences in viral infectious agents and major differences in the infected host. While human clinical studies are limited in invasiveness, they provide major advantages, including the opportunity for much more detailed findings and clinical relevance, while obviating the need for cross-species extrapolation. In addition to neurological and cognitive evaluation of human patients, which is typically far more detailed than is possible with animals, brain effects can be examined through neuropsychological testing, electroencephalographic techniques, a growing variety of scanning methods, and autopsy studies. For example, a 1994 study of 21 amphetamine abusers used single photon emission computed tomography (SPECT) to demonstrate alterations in regional blood flow in the brain. (Kao 1994) Because human research participants interact with nursing personnel and family members, subtle neurological or psychiatric symptoms can be easily detected and reported. In contrast, in most animal studies, the subjects spend most hours out of sight of clinically trained personnel. Moreover, human studies allow the investigation of the virus relevant to NIDA's RFA, i.e., HIV. While there are some similarities between HIV and FIV, there are also major differences that are particularly relevant to Dr. Podell's study. FIV's genome is very different from that of HIV. A review published by the American Society for Microbiology described FIV's "percent similarity to HIV in nucleotide sequence" as "low": "FIV diverges from other lentiviruses throughout the genome….The structural features of the genome…indicated that FIV is more closely related to the nonprimate lentiviruses EIAV [equine infectious anemia virus], caprine arthritis encephalitis virus, and visna maedi virus than to primate lentiviruses." (Bendinelli 1995) FIV is transmitted via saliva transferred by animal bites and is not passed by sexual contact, as is HIV. (Bendinelli 1995) FIV most commonly affects the cat mid-brain and thalamus, whereas HIV most commonly affects cerebral white and deep gray matter. (Gardner 1995) It is unknown whether neurological damage of FIV is due to its direct effects on brain cells, to opportunistic infections, or both. Similarly, the extent to which these effects may differ from their human counterparts is also largely unknown. The result of these differences in both the host species and the viral species is that the applicability of any findings to human illness is a matter of conjecture. Had the ILACUC required an adequate search for alternative research methods, it would have had the opportunity to weigh the ethical and practical advantages of these research methods: 1. Studies of HIV-Positive Humans Using Amphetamines as Drugs of Abuse. Amphetamines act via dopamine release. In HIV-positive individuals, these drugs are believed to accelerate the compromise of dopaminergic neuronal function. Clinical studies of HIV-positive individuals using amphetamines and other drugs have suggested that drugs and HIV may produce combined or synergistic neurotoxic effects. (Bouwman 1998, Bell 1998, Nath 2000) HIV-positive individuals who also use recreational drugs have been recruited in studies using batteries of neuropsychological tests. (Bornstein 1993) As one example of a study of the interaction of HIV and methamphetamine use in humans, NIDA is currently supporting the research of Dr. J.H. Atkinson of the University of California at San Diego, in which methamphetamine-dependent, HIV-positive humans are examined for neurological and cognitive function, among other clinical features, with a particular eye on medication compliance. The study includes a three-arm randomized clinical trial comparing the efficacy of usual medical care to two alternatives (adherence training alone, and adherence training along with stimulant relapse prevention) for facilitating adherence to anti-retroviral medications in this population. The study also relates adherence to neurological and cognitive status, psychiatric disorders, and use of medication and illicit drugs. Such a research design obviates the difficulties of relating cat findings to humans or FIV-related findings to HIV, in addition to its humane advantages. Given that neurological and cognitive status can be readily and ethically ascertained in HIV-positive humans, a full justification for substituting cats for humans and FIV for HIV is an essential part of the process of seeking approval for animal use as well as seeking federal funds. Skepticism regarding the relevance of cat and FIV studies to human disease is also appropriate and may guide investigators and reviewers toward other methods. 2. Studies of HIV-Positive Humans Participating in Clinical Trials. Dextroamphetamine has been used as an antidepressant in research trials and in clinical practice when rapid onset of action and activating effects are desired. Individuals with AIDS and depression who were treated with dextroamphetamine have been studied in clinical reports, chart reviews, and a recent prospective trial at the New York Psychiatric Institute that included a two-year follow-up. (Wagner 1997) As described above for studies of methamphetamine-dependent individuals, clinical trials permit the characterization of subtle neurological signs and symptoms that would be missed in an animal study.
3. Pathological Examinations. Autopsy studies allow the gross and microscopic examination of brain tissue. (Reyes 1991) They also provide useful data on the combined effects of drugs and HIV. For example, in a study of 450 autopsies of individuals with AIDS, those with a history of drug abuse were more likely to demonstrate HIV encephalitis, progressive multifocal leukoencephalopathy, bacterial infections, and hepatic encephalopathy. (Jellinger 2000) Other studies have focused on other aspects of brain and spinal cord pathology in individuals affected by both HIV and drug abuse. (Shepherd 1999) 4. Study of Neural Tissues. While human clinical studies have been the primary line of research in this area, the synergistic effects of HIV and recreational drugs, including amphetamines, have also been examined in human tissues. (Nath 2000) Similarly, the combined effects of HIV and other drugs of abuse have been investigated in neuroblastoma and glioblastoma cell lines. (Koutsilieri 1997) Dr. Podell's responsibilities included conducting an adequate search that would have identified these methods. If he so chose, he could have argued against the use of clinical research methods or other techniques, but he cannot simply neglect them. He is required to justify why he chose not to pursue such studies. The Animal Care Resource Guide states, "If a database search or other source identifies a bona fide alternative method (one that could be used to accomplish the goals of the animal use proposal), the written narrative should justify why this alternative was not used." In his NIH application and OSU ILACUC questionnaire, Dr. Podell described what he saw as merits of a cat model, but did not evaluate his choice in light of the methods described above. It appears that Dr. Podell chose a research method tailored to his limitations and preferences. As a veterinarian interested in FIV, rather than HIV, he asserted that his new experiment was designed to advance the study of HIV, but he apparently did not even consider that human studies would be more appropriate. The fact that he might not be qualified to execute such studies is not a justification for an inappropriate method. Animal Suffering and Fatality We believe there is evidence that Dr. Podell has understated the degree of stress imposed on the cats in his experiments. As noted above, he subjects the animals in his laboratory to a variety of stressful and invasive procedures. While he proposed that all "procedures" would be done under sedation or anesthesia, this is an inadequate assurance. Such measures do not mitigate the suffering caused by FIV infection itself, drug administration, caging, and manipulation. All of Dr. Podell's subjects are ultimately killed. In a videotape accompanying his NIH grant application, a copy of which is enclosed, Dr. Podell shows a cat with marked stereotypical movements and asserts that this gross behavioral abnormality is a graphic depiction of FIV's effects. If that is the case, sedation and anesthesia are not useful means of mitigating whatever stress accompanies these neurological signs. However, it is equally plausible that the behavioral abnormality shown is the result, not of FIV, but of the stresses of chronic confinement, isolation, and fear. It is not clear that Dr. Podell evaluated the causes of this abnormal behavior or considered how his procedures for animal use and confinement may have contributed to it. An OSU Laboratory Animal Disposition Form dated May 1, 2001, a copy of which is enclosed, shows that one of the cats used by Dr. Podell procured on December 7, 2000, was "found dead" without any further explanation, raising questions about the treatment of the animals and the level of monitoring they receive. As the ILACUC is also charged with monitoring ongoing experiments, the ILACUC's appropriate response upon learning of this fatality was an immediate investigation into the circumstances surrounding its occurrence. To the best of PCRM's knowledge, however, no action was taken by the ILACUC regarding this death. Finally, had the ILACUC been acting in compliance with federal regulations, its appropriate response to Dr. Podell's application would have been to require a more vigorous search for alternatives prior to approving the protocol. Conclusion The OSU ILACUC failed to require Dr. Podell to search for alternatives to the use of animals in requesting approval for protocol No. 00A0066, "A Feline Model of NeuroAIDS and Drug Abuse." Both Dr. Podell's ILACUC questionnaire and his NIH grant application show that he did not search for alternatives to using animals and did not even attempt to evaluate, let alone confirm, that alternatives to using animals were not available. He merely performed a limited search for duplication, which is a separate and independent requirement unrelated to the search for alternatives under federal regulations. Further, not only did he fail to search for alternatives to animal use, but Dr. Podell also neglected available methods that are clearly better suited for advancing the stated research goals and relevant animal welfare mandates. The statutory requirement to search for alternatives was not included in the Animal Welfare Act to serve as mere symbolism of Congress' concern for animals used in research. This requirement was included because Congress intended to obligate investigators and research facilities to reduce the use of, as well as the pain and distress imposed upon, animals used in research. The apparent lip service that the OSU ILACUC and Dr. Podell have given to this very serious mandate is inexcusable. It is therefore incumbent upon APHIS—as the government agency charged with implementing Congress' intent to reduce the reliance on animals in medical research and to ensure to the extent possible that they are treated humanely—to immediately initiate an investigation into the charges made herein. PCRM hereby requests that an impartial panel, including experts in public health and animal welfare, perform the investigation. Finally, PCRM requests that APHIS take steps to suspend any further activities under this protocol until completion of such investigation. Thank you for your serious and prompt attention to this matter. Sincerely, Mindy S. Kursban Enclosures Literature Cited: |
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