Novel Therapies, High-Risk Pediatric Research, and the Prospect of Benefit: Learning from the Ethical Disagreements

Abstract

Despite recent efforts by the US Food and Drug Administration (FDA) to improve the quality and quantity of clinical research data,1Benjamin DK Smith PB Sun MJ Murphy MD Avant D Mathis L et al.Safety and transparency of pediatric drug trials.Arch Pediatr Adolesc Med. 2009; 163: 1080-1086Crossref PubMed Scopus (61) Google Scholar two-thirds of drugs prescribed currently to children have not been studied for safety and efficacy in pediatric populations, and information on the efficacy and safety of drugs in children is not methodically collected and analyzed.2Noah BA Just a spoonful of sugar: drug safety for pediatric populations.J Law Med Ethics. 2009; 37: 280-291Crossref PubMed Scopus (5) Google Scholar According to some studies, the majority of pediatric drugs prescribed for children involve unlicensed drugs or off-label prescribing across all medication categories.3Bazzano AT Mangione-Smith R Schonlau M Suttorp MJ Brook RH Off-label prescribing to children in the United States outpatient setting.Acad Pediatr. 2009; 9: 81-88Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar There is evidence of a greater risk of a severe adverse drug reaction occurring in association with the off-label or unlicensed use of drugs in children.4Fabiano V Mameli C Zuccotti GV Adverse drug reactions in newborns, infants and toddlers: pediatric pharmacovigilance between present and future.Expert Opin Drug Saf. 2012; 11: 95-105Crossref PubMed Scopus (31) Google Scholar Obtaining safety and efficacy information on pediatric therapies requires systematic data collection and clinical research trials. Conducting research with human beings requires the balancing of two important, and sometimes conflicting, aims: ensuring access to the potential benefits that scientific research can offer and protecting human subjects from research risks and harms. This tension is all the more salient in pediatric research. Children's cognitive, psychological, and social immaturity limits their ability to understand what is involved in a research trial and to make sound decisions about participation. Because of children's vulnerability, federal regulations mandate that institutional review boards (IRBs) apply additional protections before they can approve pediatric research; such regulations allow IRBs to approve only research that either offers the prospect of direct benefit to the individual children participating or involves minimal risk or a minor increase over minimal risk. Both the category of research that involves minimal risk and the one involving a minor increase over minimal risk have received a significant amount of attention.5Wendler D Emanuel EJ What is a “minor” increase over minimal risk?.J Pediatr. 2005; 147: 575-578Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar,6Ross LF Nelson RM Pediatric research and the federal minimal risk standard.JAMA. 2006; 295: 759PubMed Google Scholar,7Fisher CB Kornetsky SZ Prentice ED Determining risk in pediatric research with no prospect of direct benefit: time for a national consensus on the interpretation of federal regulations.Am J Bioeth. 2007; 7: 5-10Crossref PubMed Scopus (63) Google Scholar,8Iltis A Pediatric research posing a minor increase over minimal risk and no prospect of direct benefit: challenging 45 CFR 46.406.Account Res. 2007; 14: 19-34Crossref PubMed Scopus (10) Google Scholar With some exceptions,9Ross L Phase I research and the meaning of direct benefit.J Pediatr. 2006; 149: S20-S24Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar,10US Food and Drug Administration. Pediatric Ethics Subcommittee of the Pediatric Advisory Committee <http://www.fda.gov/ohrms/dockets/ac/oc08.html#pes>(2008)Google Scholar however, the category that concerns high-risk pediatric research with the prospect of direct benefit has been subjected to less scrutiny. Moreover, although there are significant disagreements over whether phase I trials can be said to offer a “prospect of direct benefit,”11King NM Defining and describing benefit appropriately in clinical trials.J Law Med Ethics. 2000; 28: 332-343Crossref PubMed Scopus (199) Google Scholar,12Agrawal M Emanuel EJ Ethics of phase 1 oncology studies—reexamining the arguments and data.JAMA. 2003; 290: 1075-1082Crossref PubMed Scopus (163) Google Scholar,13Horstmann E McCabe MS Grochow L Yamamoto S Rubinstein L Budd T et al.Risks and benefits of phase 1 oncology trials, 1991 through 2002.N Engl J Med. 2005; 352: 895-904Crossref PubMed Scopus (375) Google Scholar,14Joffe S Miller FG Rethinking risk–benefit assessment for phase I cancer trials.J Clin Oncol. 2006; 24: 2987-2990Crossref PubMed Scopus (64) Google Scholar,15Markman M “Therapeutic intent” in phase 1 oncology trials—a justifiable objective.Arch Intern Med. 2006; 166: 1446-1448Crossref PubMed Scopus (14) Google Scholar,16Khandekar J Khandekar M Phase 1 clinical trials—not just for safety anymore?.Arch Intern Med. 2006; 166: 1440-1441Crossref PubMed Scopus (9) Google Scholar,17Anderson JA Kimmelman J Extending clinical equipoise to phase 1 trials involving patients: unresolved problems.Kennedy Inst Ethics J. 2010; 20: 75-98Crossref PubMed Scopus (27) Google Scholar much of that discussion has taken place in the context of trials involving competent adults rather than children, and much of it centers on oncology trials. We focus here on high-risk pediatric research with the prospect of direct benefit and point out some aspects that have raised significant debate. In particular, we call attention to disagreements related to two essential aspects of this type of research: (i) determining what constitutes a “prospect of direct benefit” in phase I trials that involve gene transfer technologies and (ii) assessing when in these trials the risk is justified by the anticipated benefit to the participant children. Although much of our discussion is applicable to other types of high-risk pediatric trials, as an example of the dilemma this type of research poses we use pediatric trials that involve gene transfer technologies. We focus on clinical trials for late infantile neuronal ceroid lipofuscinosis (LINCL). Exploring the ethical implications of some of these disagreements might identify resources for determining how best to deal with the ethical concerns at stake in high-risk pediatric research. We thus offer some recommendations for responding to these concerns. Most people would agree that research with children is needed to improve pediatric medicine. As with any research involving human subjects, current research guidelines, in both the United States and abroad, attempt to address this need by permitting the enrollment of children in research when it offers an appropriate risk–benefit balance.18Blake V Joffe S Kodish E Harmonization of ethics policies in pediatric research.J Law Med Ethics. 2011; 39: 70-78Crossref PubMed Scopus (8) Google Scholar If the research offers no prospect of direct benefit but involves a sufficiently low degree of risk, the requirement to balance risks and benefits calls attention to the need to assess the likelihood that the research will produce generalizable knowledge that is relevant to children's health or to particular diseases or conditions affecting children. However, although IRBs can approve research with adults that involves greater than minimal risk without the prospect of direct benefit, federal regulations for pediatric research, in accordance with recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, require that IRBs use a stricter standard.19Kopelman LM Children as research subjects: moral disputes, regulatory guidance, and recent court decisions.Mt Sinai J Med. 2006; 73: 596-604PubMed Google Scholar Pediatric research that does not offer the prospect of direct benefit is approvable by IRBs provided that the risks are sufficiently low (Table 1). Specifically, Title 45 of the Code of Federal Regulations, Part 46, Subpart D (Title 21, Part 50, Subpart D, for research involving US Food and Drug Administration (FDA) regulated products), allows pediatric research without the prospect of direct benefit when the research involves minimal risk (§46.404/50.51) and the researchers obtain the child's assent and permission from at least one parent or guardian. It also allows research with no prospect of direct benefit that involves a greater than minimal risk (§46.406/50.53) provided that (i) the risk represents a minor increase over minimal risk; (ii) the intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; (iii) the intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition that is of vital importance for the understanding or amelioration of the subjects’ disorder or condition; and (iv) adequate provisions are made for soliciting assent of the children and permission of their parents or guardians.Table 1Research involving children that the DHHS/FDA is permitted to fund or conductCategory (CFR)Level of riskProspect of direct benefit?Parental permissionAssent from childaAn institutional review board (IRB) may waive assent for certain ages of children if it determines that the child cannot reasonably be consulted or that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research.§ 46. 404; 50. 51No greater than minimal riskNot neededOne parentbAn IRB can also require permission from both parents/guardians.Yes§ 46. 405; 50. 52 Greater than minimal risk but presenting the prospect of direct benefit to the individual subjectsThe risk must be justified by the anticipated benefit to the subjectsNecessary, and the relationship of the anticipated benefit to the risk must be at least as favorable to the subjects as that presented by available alternative approachesOne parentbAn IRB can also require permission from both parents/guardians.Yes§ 46. 406; 50. 53Minor increase over minimal risk The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situationsNot needed, but research must be likely to yield generalizable knowledge about the subjects' disorder or condition that is of vital importance for the understanding or amelioration of the subjects' disorder or conditionTwo parentsYes§ 46. 407; 50. 54Not definedNot needed, but research must present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of childrenTwo parentsYesCFR, Code of Federal Regulations; DHHS/FDA, US Department of Health and Human Services/US Food and Drug Administration.From 45 CFR § 46. 404-407/21 CFR §50. 51-54.a An institutional review board (IRB) may waive assent for certain ages of children if it determines that the child cannot reasonably be consulted or that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research.b An IRB can also require permission from both parents/guardians. Open table in a new tab CFR, Code of Federal Regulations; DHHS/FDA, US Department of Health and Human Services/US Food and Drug Administration. From 45 CFR § 46. 404-407/21 CFR §50. 51-54. Sometimes, however, research can involve a greater than a minor increase over minimal risk. This type of research is approvable by IRBs only when it offers the prospect of direct benefit to the children participating (§46.405/50.52). Moreover, such research can be approved provided that (i) the risk is justified by the anticipated benefit to the participant children; (ii) the relationship of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternatives; and, as with prior categories, (ii) adequate provisions are made for soliciting assent of the children and permission of their parents or guardians. Research that involves greater than minimal risk with no prospect of direct benefit cannot be approved by IRBs. However, if this type of research, called “research otherwise not approvable” (§46.407/50.54), presents an opportunity to understand, prevent, or alleviate serious health problems, it can be approved by the Secretary of the US Department of Health and Human Services (DHHS) or the FDA Commissioner, after receiving a recommendation from an expert committee (Figure 1). Early-phase gene transfer trials present a good illustration of the ethical difficulties related to the assessment of risks and potential benefits (Tables 2 and 3). These trials usually address rare, fatal or very serious diseases for which few or no other alternatives exist, are associated with significant risks (including death), and often involve highly novel approaches and surgical procedures.20Cavazzana-Calvo M Hacein-Bey S de Saint Basile G Gross F Yvon E Nusbaum P et al.Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease.Science. 2000; 288: 669-672Crossref PubMed Scopus (2232) Google Scholar,21Hacein-Bey-Abina S von Kalle C Schmidt M Le Deist F Wulffraat N McIntyre E et al.A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency.N Engl J Med. 2003; 348: 255-256Crossref PubMed Scopus (1611) Google Scholar,22Hacein-Bey-Abina S Von Kalle C Schmidt M McCormack MP Wulffraat N Leboulch P et al.LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.Science. 2003; 302: 415-419Crossref PubMed Scopus (3001) Google Scholar,23Worgall S Sondhi D Hackett NR Kosofsky B Kekatpure MV Neyzi N et al.Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA.Hum Gene Ther. 2008; 19: 463-474Crossref PubMed Scopus (326) Google Scholar For instance, LINCL, an autosomal recessive lysosomal storage disease that affects the brain and retina,24Mole SE Williams RE Goebel HH The Neuronal Ceroid Lipofuscinoses (Batten Disease). Oxford University Press, Oxford, UK2011Crossref Google Scholar is inevitably fatal in childhood, following progressive neurological deterioration. There is currently no treatment for LINCL other than management of symptoms. Clinical trials for this disease have involved the administration of an AAV2hCLN2 vector23Worgall S Sondhi D Hackett NR Kosofsky B Kekatpure MV Neyzi N et al.Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA.Hum Gene Ther. 2008; 19: 463-474Crossref PubMed Scopus (326) Google Scholar directly to the central nervous system (CNS) of children with LINCL in a neurosurgical procedure involving general anesthesia, six burr holes, catheter insertion, and infusion of the vector in a total of 12 sites over several hours.Table 2Benefits of gene transfer intervention in early-phase clinical trials of nonmalignant disease in the pediatric populationDiseaseTherapeutic testedType of diseaseBenefit/outcomeRef.X-SCIDEx vivo transduction of hematopoietic stem cells by retroviral gene transfer in childrenImmunodeficiencyCorrected immunodeficiency associated with X-SCID20Cavazzana-Calvo M Hacein-Bey S de Saint Basile G Gross F Yvon E Nusbaum P et al.Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease.Science. 2000; 288: 669-672Crossref PubMed Scopus (2232) Google Scholar, 56Gaspar HB Parsley KL Howe S King D Gilmour KC Sinclair J et al.Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector.Lancet. 2004; 364: 2181-2187Abstract Full Text Full Text PDF PubMed Scopus (582) Google ScholarADA-SCIDEx vivo transduction of hematopoietic stem cells by retroviral gene transfer in childrenImmunodeficiencyRestoration of immune function25Aiuti A Slavin S Aker M Ficara F Deola S Mortellaro A et al.Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning.Science. 2002; 296: 2410-2413Crossref PubMed Scopus (981) Google Scholar, 57Aiuti A Cattaneo F Galimberti S Benninghoff U Cassani B Callegaro L et al.Gene therapy for immunodeficiency due to adenosine deaminase deficiency.N Engl J Med. 2009; 360: 447-458Crossref PubMed Scopus (816) Google ScholarLeber congenital amaurosisAdeno-associated viral vector-mediated gene transfer to the eyeBlindnessImprovement in visual function58Jacobson SG Cideciyan AV Ratnakaram R Heon E Schwartz SB Roman AJ et al.Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years.Arch Ophthalmol. 2012; 130: 9-24Crossref PubMed Scopus (491) Google Scholar, 59Simonelli F Maguire AM Testa F Pierce EA Mingozzi F Bennicelli JL et al.Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration.Mol Ther. 2010; 18: 643-650Abstract Full Text Full Text PDF PubMed Scopus (464) Google ScholarWiskott-Aldrich syndromeEx vivo transduction of hematopoietic stem cells by retroviral gene transfer in childrenImmunodeficiencyImproved immune reconstitution26Boztug K Schmidt M Schwarzer A Banerjee PP Diez IA Dewey RA et al.Stem-cell gene therapy for the Wiskott-Aldrich syndrome.N Engl J Med. 2010; 363: 1918-1927Crossref PubMed Scopus (435) Google Scholarβ-ThalassemiaaThe subject was 18 years old.Ex vivo transduction of bone marrow cells by lentiviral gene transferHemoglobinopathyHemoglobin levels increased such that transfusions not required40Cavazzana-Calvo M Payen E Negre O Wang G Hehir K Fusil F et al.Transfusion independence and HMGA2 activation after gene therapy of human b-thalassaemia.Nature. 2010; 467: 318-322Crossref PubMed Scopus (1035) Google ScholarLate infantile neuronal ceroid lipofuscinosisAdeno-associated viral vector-mediated gene transfer to the CNS of childrenNeurodegenerativeSlowing of the rate of neurological decline23Worgall S Sondhi D Hackett NR Kosofsky B Kekatpure MV Neyzi N et al.Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA.Hum Gene Ther. 2008; 19: 463-474Crossref PubMed Scopus (326) Google ScholarX-linked adrenoleukodystrophyEx vivo transduction of hematopoietic stem cells by lentiviral gene transfer in childrenNeurodegenerativeHalting of progressive cerebral demyelination27Cartier N Hacein-Bey-Abina S Bartholomae CC Veres G Schmidt M Kutschera I et al.Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.Science. 2009; 326: 818-823Crossref PubMed Scopus (1177) Google ScholarAbbreviations: ADA-SCID, adenosine deaminase-mediated severe combined immunodeficiency; CNS, central nervous system; X-SCID, X-linked severe combined immunodeficiency.This is a partial list of benefits in the gene therapy field as it relates to the pediatric population in the last decade. It includes many of the diseases listed in a table in the review by Kaiser.60Kaiser J Clinical research. Gene therapists celebrate a decade of progress.Science. 2011; 334: 29-30Crossref PubMed Scopus (16) Google Scholara The subject was 18 years old. Open table in a new tab Table 3Serious drug-related adverse events in early-phase gene transfer clinical trials of nonmalignant disease in the pediatric populationDiseaseTherapeutic testedType of diseaseSerious drug-related adverse events/resolutionRef.X-SCIDEx vivo transduction of hematopoietic stem cells by retroviral gene transfer in childrenImmunodeficiencyLymphocytic leukemia due to vector integration21Hacein-Bey-Abina S von Kalle C Schmidt M Le Deist F Wulffraat N McIntyre E et al.A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency.N Engl J Med. 2003; 348: 255-256Crossref PubMed Scopus (1611) Google Scholar, 22Hacein-Bey-Abina S Von Kalle C Schmidt M McCormack MP Wulffraat N Leboulch P et al.LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.Science. 2003; 302: 415-419Crossref PubMed Scopus (3001) Google ScholarOrnithine transcarbamylaseaThis trial involved adult subjects, but some of them were 18 years old.Adenovirus-mediated gene therapyMetabolic disorderDeath of an 18-year-old subject39Raper SE Chirmule N Lee FS Wivel NA Bagg A Gao GP et al.Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase-deficient patient following adenoviral gene transfer.Mol Genet Metab. 2003; 80: 148-158Abstract Full Text Full Text PDF PubMed Scopus (1176) Google Scholarβ-ThalassemiabThe subject was 18 years old.Ex vivo transduction of bone marrow cells by lentiviral gene transferHemoglobinopathyThe inserted gene may have turned on growth signals, raising potential for cancer.61Hacein-Bey-Abina S Hauer J Lim A Picard C Wang GP Berry CC et al.Efficacy of gene therapy for X-linked severe combined immuno­deficiency.N Engl J Med. 2010; 363: 355-364Crossref PubMed Scopus (499) Google ScholarAbbreviation: X-SCID, X-linked severe combined immunodeficiency.This is a partial list of serious adverse events in the gene therapy field as it relates to the pediatric population in the last decade.a This trial involved adult subjects, but some of them were 18 years old.b The subject was 18 years old. Open table in a new tab Abbreviations: ADA-SCID, adenosine deaminase-mediated severe combined immunodeficiency; CNS, central nervous system; X-SCID, X-linked severe combined immunodeficiency. This is a partial list of benefits in the gene therapy field as it relates to the pediatric population in the last decade. It includes many of the diseases listed in a table in the review by Kaiser.60Kaiser J Clinical research. Gene therapists celebrate a decade of progress.Science. 2011; 334: 29-30Crossref PubMed Scopus (16) Google Scholar Abbreviation: X-SCID, X-linked severe combined immunodeficiency. This is a partial list of serious adverse events in the gene therapy field as it relates to the pediatric population in the last decade. Although phase I studies like the one for LINCL play a critical role in the translation of basic research into clinical application, they also present researchers and IRBs with the significant difficulty of determining whether such trials offer the prospect of direct benefit to the participant children. Children might benefit from participating in a clinical trial because the trial involves more careful monitoring, or some children might benefit from participating in research because such participation allows them access to medical care that they would otherwise lack. Such benefits however, are not direct but collateral benefits of research participation.11King NM Defining and describing benefit appropriately in clinical trials.J Law Med Ethics. 2000; 28: 332-343Crossref PubMed Scopus (199) Google Scholar Similarly, clinical trials usually involve aspirational benefits. These are benefits to society that result from conducting scientific research, such as generation of scientific knowledge and future improvements in treatment. However, as currently accepted, direct benefits to the children participating in research are those that result from receiving the particular intervention being tested.11King NM Defining and describing benefit appropriately in clinical trials.J Law Med Ethics. 2000; 28: 332-343Crossref PubMed Scopus (199) Google Scholar Of course, phase I trials can involve a variety of purposes and designs, and not all of them would present the same degree of difficulty when assessing the prospect of direct benefit. Nonetheless, legitimate disagreements exist about whether phase I trials that involve novel procedures, such as gene transfer, can be said to offer the prospect of direct benefit. Some of them involve epistemological disagreements about the strength of the evidence. For instance, preclinical studies provided justification for initiating several gene transfer phase I trials involving children.20Cavazzana-Calvo M Hacein-Bey S de Saint Basile G Gross F Yvon E Nusbaum P et al.Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease.Science. 2000; 288: 669-672Crossref PubMed Scopus (2232) Google Scholar,23Worgall S Sondhi D Hackett NR Kosofsky B Kekatpure MV Neyzi N et al.Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA.Hum Gene Ther. 2008; 19: 463-474Crossref PubMed Scopus (326) Google Scholar,25Aiuti A Slavin S Aker M Ficara F Deola S Mortellaro A et al.Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning.Science. 2002; 296: 2410-2413Crossref PubMed Scopus (981) Google Scholar,26Boztug K Schmidt M Schwarzer A Banerjee PP Diez IA Dewey RA et al.Stem-cell gene therapy for the Wiskott-Aldrich syndrome.N Engl J Med. 2010; 363: 1918-1927Crossref PubMed Scopus (435) Google Scholar,27Cartier N Hacein-Bey-Abina S Bartholomae CC Veres G Schmidt M Kutschera I et al.Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.Science. 2009; 326: 818-823Crossref PubMed Scopus (1177) Google Scholar In the case of LINCL, preclinical studies with rodents showed that administration of the vectors AAV2hCLN2 and AAVrh.10hCLN2 was associated with a decrease in the abnormal accumulation of storage material in CNS neurons.23Worgall S Sondhi D Hackett NR Kosofsky B Kekatpure MV Neyzi N et al.Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA.Hum Gene Ther. 2008; 19: 463-474Crossref PubMed Scopus (326) Google Scholar,28Sondhi D Hackett NR Peterson DA Stratton J Baad M Travis KM et al.Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus macaque-derived adeno-associated virus vector.Mol Ther. 2007; 15: 481-491Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar However, there is significant evidence that what are clearly encouraging results encountered in preclinical studies often fail to translate into efficacy in clinical studies.29Hackam DG Redelmeier DA Translation of research evidence from animals to humans.JAMA. 2006; 296: 1731-1732Crossref PubMed Scopus (497) Google Scholar,30Perel P Roberts I Sena E Wheble P Briscoe C Sandercock P et al.Comparison of treatment effects between animal experiments and clinical trials: systematic review.BMJ. 2007; 334: 197-200Crossref PubMed Scopus (556) Google Scholar Clearly, the biology of humans shares many commonalities with rodents and nonhuman primates, but inferences from animal models to human beings are fraught with difficulties. Reasons for this disconnect between preclinical and clinical outcomes include problems with the animal models used, poor methodological quality of animal studies, and publication bias.31Jucker M The benefits and limitations of animal models for translational research in neurodegenerative diseases.Nat Med. 2010; 16: 1210-1214Crossref PubMed Scopus (252) Google Scholar,32de Jong M Maina T Of mice and humans: are they the same? Implications in cancer translational research.J Nucl Med. 2010; 51: 501-504Crossref PubMed Scopus (129) Google Scholar,33van der Worp HB Macleod MR Preclinical studies of human disease: time to take methodological quality seriously.J Mol Cell Cardiol. 2011; 51: 449-450Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Of course, it could be the case that, for some phase I trials, the preclinical studies used as evidence to argue for a prospect of direct benefit are strong, but the epistemic difficulty of determining when such is the case might still be present. Others, however, argue that, rather than considerations about the amount or quality of evidence for the experimental procedure, what are important for determining whether a trial offers the prospect of direct benefit are the intentions of investigators when conducting research. For these commentators, the intentions of the researchers are morally relevant, and they should be taken into account when making determinations about anticipated benefits.34Weijer C Miller PB When are research risks reasonable in relation to anticipated benefits?.Nat Med. 2004; 10: 570-573Crossref PubMed Scopus (143) Google Scholar Clinical research is thought to often contain a mixture of procedures. Some of those procedures (e.g., drugs, biologics, and surgical and behavioral interventions) are administered with therapeutic intent, whereas others (e.g., venipuncture for pharmacokinetic drug levels, additional imaging procedures, and genetic analysis not used in clinical practice) are used solely to answer a particular research question. Given the moral relevance of researchers’ intentions when using therapeutic and nontherapeutic procedures, such interventions require different moral standards of evaluation. Therapeutic procedures in particular must meet the ethical standard of clinical equipoise.35Freedman B Equipoise and the ethics of clinical research.N Engl J Med. 1987; 317: 141-145Crossref PubMed Scopus (1695) Google Scholar Under this view, clinical equipoise requires that at the beginning of a trial there exists a state of honest, professional disagreement in the community of expert practitioners as to the preferred treatment. In at least some phase I trials invol