It is an FDA requirement that the“first in human" dose be based on pre-clinical animal model efficacy and safety testing to ensure a safe entry into Phase I clinical trials. Pre-clinical safety and efficacy models range from mouse to non-human primates. Interspecies scaling of pharmacokinetic parameters is therefore important for predicting drug doses in human clinical trials, although it continues to be less than optimal. Understanding the disposition of the compound in different species through in vitro and in vivo experiments is necessary to ensure appropriate species are selected for human estimates. Data for three imaging agents and a pharmacological stress agent (Oncology tumor agent (DPC-A80351), Thrombus agent (DMP-444), Infection agent (RP-517) Pharmacological stress agent (DPC-A78445-00)) that entered clinical trials and an imaging agent being developed (RP845), were assessed for scaling accuracy. Initially, pharmacokinetic data from animal models were used to extrapolate to human though body weight allometric scaling. Subsequently, the impact of adjusting for plasma protein binding and the impact of metabolic stability in the different models were examined. Allometric scaling of animal pharmacokinetic parameters (clearance (CL), half-life (t½) and volume of distribution (Vdss)) achieved a prediction of the human pharmacokinetic parameter within 13 to 109% of the observed values. This prediction was further improved by adjusting for plasma protein binding of the drug, and achieved an estimate within 5 to 57% of the clinically observed values. Since the parent compound was the dominant species (>95%) in the circulation, metabolic stability was not used as a correction factor. Weight based allometric scaling was further examined for an atherosclerotic plaque targeted radiopharmaceutical imaging agent, RP845-Tc-99m, currently in development. Pharmacokinetic parameters were determined in mouse, rat and rabbit followed by allometric scaling to predict the non-human primate values. Differences between predicted versus observed non-human primate Cl, t½ and Vdss were 40%, 52% and 8%, respectively. Correcting for plasma protein binding improved the prediction for Cl and t½ to within 12 and 3 %, respectively. The Vdss prediction, however became less accurate (38% difference). Since blood clearance is the major parameter in predicting human dose, the improvement from 40% to 12% was important. The plasma protein binding adjusted animal data was then used with allometric scaling to predict human CL, t½ and Vdss. The predicted values were 7.6 mL/min/kg, 70.6 minutes and 0.87 L/kg respectively. Based on the predicted human blood clearance and the dose required to image atherosclerosis in a rabbit model, the estimated human dose would be unacceptably high. This demonstrates how allometric scaling can be used in research projects to assess clinical feasibility. The impact of metabolism differences influencing the reliability of various species to predict for man was highlighted by DPC-A78445-00. DPC-A78445-00 is being developed as an alternative to exercise in myocardial perfusion imaging for the evaluation of coronary artery disease. DPC-A78445-00 was rapidly metabolized to the carboxylic acid by mouse and rat blood in vitro and in vivo, however longer stability was observed in the dog. In vitro human blood data was consistent with the dog, suggesting that mouse and rat would not be representative species. DPC-A78445-00 plasma protein binding was at a similar, moderate level in rat, dog and human plasma and metabolism by hepatocytes was similar in dog and human. Phase I human clinical trial testing determined the area under the blood concentration-time curve (AUC) and clearance predicted by the dog were within 32% of the human values. Overall, body weight based allometric scaling of pharmacokinetic parameters from animal models, when corrected for plasma protein binding, yielded reliable predictions of the human pharmacokinetics (within 50%) for radiopharmaceutical imaging agent. However, although predictive scaling from animal data can give insight into feasibility of compounds working in human, it is important to identify species differences with respect to metabolic stability. This allometric scaling method provides an additional tool to better predict doses in human for novel Medical Imaging agents.

Qui sont les personnes vulnérables, à quoi sont-elles vulnérables en matière d’essais cliniques et comment sont-elles protégées par le droit européen ? C’est en clarifiant le concept de vulnérabilité qu’il est possible de donner une ébauche de réponse à cette problématique fondamentalement éthique. En examinant les différents types de risques propres aux essais cliniques, il est possible de distinguer la vulnérabilité décisionnelle du participant aux essais (liée à son inaptitude à défendre ses intérêts et à l’exposition aux abus et à l’exploitation qui en découle) ; de la vulnérabilité de santé du futur patient (liée à sa condition médicale et sa représentation dans les essais pour éviter qu’à une faiblesse initialement clinique ne vienne s’ajouter une marginalisation par l’absence de recherches et de données fiables). Bien que très différents, ces deux types de vulnérabilité sont trop souvent confondus ou assimilés car fréquemment présents chez une même personne, l’exemple par excellence étant celui des enfants, juridiquement incapables et physiologiquement différents des adultes. Sans prétendre apporter de solution idéale, cette thèse pose un regard éthique et critique sur ce que permet (ou non), à ce propos, le droit européen - Conseil de l’Europe comme Union européenne. Elle permet de mettre en valeur les progrès considérables de ce dernier dans la protection des personnes vulnérables, de souligner les moyens et instruments qui s’y sont révélés efficaces et de susciter la réflexion sur les voies d’amélioration de la protection des personnes vulnérables dans les essais cliniques et plus généralement sur les enjeux de l’insertion de la notion de vulnérabilité en droit / Who are vulnerable people? Why are they vulnerable in clinical trials? How are they protected by European law? By clarifying the concept of vulnerability it will be possible to get a preliminary answer to this ethical dilemma. Examining the different types of risks to which a person can be vulnerable will it be possible to distinguish decisional vulnerability (inability to defend one’s own interests and the resulting exposure to abuse and exploitation of the potential participant), and health vulnerability (risks of violation of health and safety when ingesting a potentially dangerous experimental medicine when the patient has not been properly represented in clinical trials). Although very different, those two types of vulnerability are often conflated or assimilated with one another because they are frequently present in a single person, the best example being children, both legally incapacitated and physiologically different than adults. Without claiming to bring an ideal solution to these complex dilemmas, this thesis advances an ethical and critical perspective on European law – Council of Europe and European Union. It stresses the considerable progress made in protecting vulnerable people, highlights the means and instruments that are most efficacious, and stimulates reflection on how to further ameliorate the protection of vulnerable people in clinical trials

Sephton, Carmen Ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 127-144). / Abstracts in English and Chinese. / Chapter A. --- Acknowledgement --- p.ii / Chapter B. --- Abstract in English --- p.iii / Chapter C. --- Abstract in Chinese --- p.v / Chapter D. --- Table of Contents --- p.vii / Chapter E. --- List of Abbreviations --- p.xii / Chapter D. --- Table of Contents / Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- Basic background of TCM --- p.3 / Chapter 1.2 --- Choosing TCM Over Western Medication --- p.6 / Chapter 1.3 --- TCM Clinical Trials --- p.7 / Chapter 1.4 --- Evidence Based Medicine and Good Clinical Practice --- p.11 / Chapter 1.5 --- Outline of ICH GCP guidelines used for evaluation --- p.15 / Chapter 2. --- Aim and Objectives --- p.18 / Chapter 3. --- Method --- p.19 / Chapter 3.1 --- Rational for choosing the two studies for comparison --- p.21 / Chapter 3.2 --- Literature Search --- p.25 / Chapter 4. --- Method - Traditional Chinese Medicine clinical trial --- p.27 / Chapter 4.1 --- Protocol Development --- p.27 / Chapter 4.2 --- Consent Form Development --- p.28 / Chapter 4.3 --- Ethics Committee Submission and Approval --- p.29 / Chapter 4.4 --- Case Report Form Development --- p.29 / Chapter 4.5 --- Investigator Folder Development --- p.32 / Chapter 4.6 --- GCP Documentation Collection and Development --- p.33 / Chapter 4.6.1 --- Curriculum Vitae Collection --- p.33 / Chapter 4.6.2 --- Site Personnel Log --- p.34 / Chapter 4.6.3 --- Subject Screening Log --- p.34 / Chapter 4.6.4 --- Subject Identification Code List --- p.35 / Chapter 4.6.5 --- Subject Enrolment Log --- p.35 / Chapter 4.7 --- Medication --- p.36 / Chapter 4.7.1 --- Capsules --- p.36 / Chapter 4.7.2 --- Randomisation Code --- p.39 / Chapter 4.7.3 --- Labelling of Study Medication --- p.40 / Chapter 4.7.4 --- Storage --- p.40 / Chapter 4.7.5 --- Drug Accountability --- p.40 / Chapter 4.8 --- Investigator Brochure --- p.41 / Chapter 4.9 --- Monitoring --- p.41 / Chapter 5. --- Method - Western medication clinical trial --- p.42 / Chapter 5.1 --- Protocol Development --- p.42 / Chapter 5.2 --- Consent Form Development --- p.43 / Chapter 5.3 --- Ethics Committee Submission and Approval --- p.43 / Chapter 5.4 --- Case Report Form Development --- p.43 / Chapter 5.5 --- Investigator Folder Development --- p.44 / Chapter 5.6 --- GCP Documentation Collection and Development --- p.44 / Chapter 5.6.1 --- Curriculum Vitae Collection --- p.44 / Chapter 5.6.2 --- Site Personnel Log --- p.45 / Chapter 5.6.3 --- Subject Screening Log --- p.45 / Chapter 5.6.4 --- Subject Identification Code List --- p.45 / Chapter 5.6.5 --- Subject Enrolment Log --- p.45 / Chapter 5.7 --- Medication --- p.46 / Chapter 5.7.1 --- Tablets --- p.46 / Chapter 5.7.2 --- Randomisation Code --- p.46 / Chapter 5.7.3 --- Labelling of Study Medication --- p.47 / Chapter 5.7.4 --- Storage --- p.47 / Chapter 5.7.5 --- Drug Accountability --- p.48 / Chapter 5.8 --- Investigator Brochure --- p.48 / Chapter 5.9 --- Monitoring --- p.48 / Chapter 6. --- Results & Discussion --- p.49 / Chapter 6.1 --- Protocol Development --- p.49 / Chapter 6.2 --- Consent Form Development --- p.59 / Chapter 6.3 --- Case Report Form Development --- p.65 / Chapter 6.4 --- Ethics Committee --- p.67 / Chapter 6.5 --- Investigator Folder Development --- p.68 / Chapter 6.6 --- GCP Documentation --- p.68 / Chapter 6.7 --- Medication --- p.69 / Chapter 6.7.1 --- Study Medication --- p.69 / Chapter 6.7.2 --- Randomisation Code and Code Break Envelops --- p.71 / Chapter 6.7.3 --- Labelling --- p.71 / Chapter 6.7.4 --- Storage --- p.73 / Chapter 6.8 --- Investigator Brochure (IB) --- p.73 / Chapter 6.9 --- Monitoring Visits --- p.75 / Chapter 6.9.1 --- Source document verification --- p.76 / Chapter 6.10 --- Results of Literature Search --- p.80 / Chapter 7. --- Discussion --- p.95 / Chapter 7.1 --- Discussion on the implementation of GCP in the two clinical trials evaluated --- p.95 / Chapter 7.2 --- Role and Importance of the Study Monitor & Results of Source Document Verification --- p.99 / Chapter 7.3 --- Blinding & randomisation procedures --- p.103 / Chapter 7.4 --- Good clinical Practice & TCM clinical trials --- p.103 / Chapter 7.5 --- Performing Literature Search in Preparation for TCM Clinical Trials --- p.110 / Chapter 7.6 --- Standardisation of Herbs and GMP Issues --- p.112 / Chapter 7.7 --- TCM Medical Practitioner (Investigator) Selection --- p.116 / Chapter 7.8 --- Method of Diagnosis --- p.117 / Chapter 7.9 --- Randomisation & Blind Assessment (placebo or control treatment) --- p.118 / Chapter 7.10 --- Adverse Events in TCM Clinical Trials --- p.122 / Chapter 7.11 --- Other Issues or Considerations & Future Work to be Performed at the CPSU --- p.122 / Chapter 8. --- Conclusion --- p.125 / Chapter 9. --- Reference List --- p.127 / Chapter 10. --- Appendices --- p.145

Aim PRECIS (PRagmatic Explanatory Continuum Indicator Summaries 2009) is a tool with a simple wheel format that trialists can use when designing their trials to improve the applicability of results but users highlighted problems. The aim of the study was to produce an improved and validated version of PRECIS, called PRECIS-2 and test this tool out with trial teams designing primary care trials. Methods Brainstorming and a 2-round Delphi survey of authors who cited PRECIS plus user-testing of candidate PRECIS-2 models was followed by validity and reliability testing of the most promising PRECIS-2 candidate using a sample of 15 trials rated by 19 different trialists. The validated PRECIS-2 tool was then used to consider the risk of bias (internal validity) and estimates of treatment effect of a matched set of explanatory (ideal conditions) and pragmatic (real world) trials. The PRECIS-2 website was also created with a database of pragmatic trials and a toolkit for trial groups. This was tested out at the Pragmatic Clinical Trials Unit (PCTU) in London with trial teams designing primary care trials. Results Forty-two people responded to the Delphi and highlighted scoring, domain choice, and tool format as issues. An expert panel of 14 in Toronto provided the basis for a PRECIS-2 model that was then user tested by 19 other methodologists and trialists. After 13 iterations, a PRECIS-2 model with 9 domains (i.e. Eligibility, Recruitment, Setting, Organisation, Flexibility Delivery, Flexibility Adherence, Follow up, Primary Outcome, Primary Analysis) was tested for validity and reliability. Inter-rater reliability was generally good, with eight of nine domains having an ICC over 0.65. Discriminant validity was reasonable for all domains, though with wide confidence intervals. Matching trials taking pragmatic (‘real world’) and explanatory (‘ideal world’) approaches was challenging but we found no indication that a pragmatic approach compromises internal validity. We were unable to extract sufficient information for a planned analysis of estimates of treatment effect. At the PCTU, the tool highlighted differences in opinion with trial team members and demonstrated convergence of opinion following discussion. There was acknowledgment that scoring of PRECIS-2 domains assisted trials teams in considering the intended audience and creation of trials relevant to practice. Useful feedback was obtained to improve the PRECIS-2 tool software for users. Conclusions PRECIS was improved by the addition of scoring and additional domains after consultation with over 80 international trialists. We have a validated PRECIS-2, in the visually appealing wheel format with 9 spokes, which is being made available through an increasingly accessed website. Work at the PCTU improved the usability of the PRECIS-2 website and demonstrated that the tool increases transparency in trial design and assists trialists in considering applicability of trial results. More matching work on the impact of design approaches on effect size is needed, and further data to support the risk of bias results would be valuable.

MSc (Med), Pharmaceutical Affairs, Faculty of Health Sciences, University of the Witwatersrand / Quality Assurance (QA) Audits are an essential component and an integral part of clinical trials. As a quality improvement tool, forming part of Good Clinical Practice (GCP) an audit can demonstrate that real efforts are being made to improve and enhance the quality of professional care to all trial subjects participating in clinical trials. Specifically, clinical research performed on the central nervous system (CNS) involves distinctive areas of concern to adherence to good clinical practice in this therapeutic area. For example an informed consent process not conducted appropriately for subjects with e.g. Schizophrenia or Alzheimer’s disease; or inter-individual rating differences in instances when different investigators (psychiatrist) assess a trial subject. A need was identified to analyze the association between the CNS indication audited and the audit findings and to perform a trend analysis that highlight re-occuring audit findings. A total of 123 CNS audit reports were obtained from the Quality Assurance Departments of Quintiles in South Africa and Europe. The audit reports were grouped into the 15 CNS indications that were audited. Five hundred and six (506) audit findings were derived from the 123 CNS audits reports. The audit findings were categorized according to GCP subject matter, regulatory requirements or Standard Operating Procedures (SOPs). The severity of audit findings was classified as critical or major. The results of this investigation suggested a need for substantial improvement in three important areas. Firstly; adherence to the study requirements inclusive of relevant Standard Operating Procedures (SOPs). Secondly the development of better defined protocols and thirdly training of monitors. Study planners and Clinical Trial Management should take a proactive role to minimize the audit findings by ensuring monitors with experience in the research field should be involved in the study. Procedures should be implemented to educate site staff. Focus should be placed on the importance of detailed source documentation, adherence to investigational product dosage requirements, the conduct of the informed consent process, and adequate study documentation maintenance.

Un essai clinique consiste en un ensemble de principes épistémologiques élevé au rang d’instrument d’action publique. Sa fonction est d’établir l’efficacité des traitements dans un cadre assurant la légitimité sociale de la production du savoir médical et pharmacologique. D’un point de vue organisationnel, il repose sur un ensemble de micro-activités administratives permettant de garantir la faisabilité d’un protocole de recherche, la sécurité des patients et la fiabilité des données produites.Cette thèse propose une analyse sociologique de cette « administration de la preuve » que sont les essais cliniques et, ainsi, de compléter les études qui se sont jusque-là essentiellement consacrées à l’étude des droits des patients, à l’activisme thérapeutique ou encore à l’organisation épistémique de la recherche. L’expression d’ « administration » renvoie d’abord aux procédés méthodologiques mobilisés durant le déroulement d’un essai pour prouver l’efficacité d’un traitement. Elle renvoie ensuite aux activités administratives déployées par la pluralité d’acteurs qui composent l’essai pour recruter des patients, coordonner des cliniciens et contrôler la production des données cliniques. Etant donné l’hétérogénéité des travailleurs investis dans un essai et les différents univers normatifs qu’ils véhiculent, les imprévus organisationnels susceptibles de compromettre le cours des choses et les relations atypiques de contrôle qui bouleversent l’économie traditionnelle des hiérarchies professionnelles, comment ces acteurs parviennent à s’inscrire dans cette organisation bureaucratique que sont les essais cliniques et quel type de solidarité sous-tend cette administration de la preuve ? Pour répondre à cette question, nous proposons de saisir la bureaucratie en personnes et en actes et de tenir compte de la matière du travail administratif, des temporalités engagées dans la mise en place et la réalisation d’un essai, ainsi que des dynamiques relationnelles qui se jouent entre les promoteurs et les investigateurs, ainsi que leur personnel de renfort. A partir d’un travail documentaire, d’observation de réunions et d’une cinquantaine d’entretiens conduits auprès d’investigateurs, de techniciens d’études cliniques, de responsables d’études cliniques, d’attachés de recherche, de méthodologistes, ou encore de biostatisticiens nous soutenons que le fonctionnement d’un essai clinique procède d’une forme de solidarité particulière : la solidarité procédurale. La notion désigne la capacité des procédures administratives (consentement, notification d’événements indésirables, etc.) à cadrer et stabiliser dans la durée les actions et interactions des différents acteurs engagés dans la réalisation d’un essai clinique et supposés suivre un protocole de recherche. Après être revenu sur l’histoire de la bureaucratisation de l’évaluation des médicaments, nous suivons pas à pas les étapes des essais, allant de la conception d’un protocole de recherche jusqu’au gel d’une base de données afin de décrire la dynamique sociale propre à la solidarité procédurale. / A clinical trial consists of a set of epistemological principles used as a public policy instrument. Its function is to establish the effectiveness of treatments within a framework that ensures the social legitimacy of the production of medical and pharmacological knowledge. From an organizational point of view, it is based on a set of micro-administrative activities to ensure the feasibility of a research protocol, patient safety and the reliability of the data produced.This thesis proposes a sociological analysis of the “administration of evidence” that clinical trials are, and thus, to complete the studies that have so far been essentially devoted to the study of patients’ rights, therapeutic activism or the epistemic organization of research. The French term “administration” refers first of all to the methodological procedures used during the conduct of a trial to prove the effectiveness of a treatment. It then refers to the administrative activities deployed by the plurality of actors in the trial to recruit patients, coordinate clinicians and control the production of clinical data. Given the heterogeneity of the workers involved in a trial and the different normative universes they convey, the organizational contingencies that may compromise the course of events and the atypical control relationships that disrupt the traditional economy of professional hierarchies, how do these actors manage to fit into the bureaucratic organization that clinical trials are and what type of solidarity underlies this administration of proof? To answer this question, we propose to approach the bureaucracy in persons and in activities and to take into account the subject matter of the administrative work, the time involved in setting up and carrying out a trial, as well as the relational dynamics that are played out between the sponsors and the investigators, as well as their support staff. Based on documentary work, observation of meetings and about fifty interviews with investigators, clinical study technicians, clinical study managers, research associates, methodologists and biostatisticians, we maintain that the functioning of a clinical trial is based on a particular form of solidarity: procedural solidarity. The notion refers to the ability of administrative procedures (consent, reporting of adverse events, etc.) to frame and stabilize over time the actions and interactions of the various actors involved in the conduct of a clinical trial and expected to follow a research protocol. After reviewing the history of the bureaucratization of drug evaluation, we follow the steps of the trials step by step, from designing a research protocol to freezing a database to describe the social dynamics of procedural solidarity.

This thesis is motivated by an adaptive design which was developed to inoculate healthy volunteers with nontypeable Haemophilus influenzae. The goal was to estimate the doses at which 50% (HCD50) and 90% (HCD90) of subjects became colonized. A fifteen-subject study was designed in two stages, with the first six subjects allocated sequentially. The design was chosen based on scientific and statistical arguments, however, due to limited time, heuristic decisions were made for expedience. This design and a number of alternative designs are evaluated in depth by simulation, under both Bayesian and frequentist criteria. In this thesis, Bayesian myopic strategies with one-step- , two-step- and three-step-look-ahead procedures are investigated. The optimal design is defined as the one with minimum expected loss where the loss is the sum of the posterior variance of the HCD50 and HCD90. The higher the expected loss, the worse the design. Designs using different prior distribution are examined. In addition, the toxicity-response relationship can also be incorporated in selecting the optimal design. A new model considering both colonization (efficacy) and adverse event (toxicity) is proposed, and design procedures developed. Furthermore, restrictions on the probability of toxicity are implemented. The results from simulations show that it is beneficial to look more steps ahead in determining the optimal dose although the benefit may not be large. The is true for both univariate (colonization) and bivariate (colonization and toxicity) models. For the bivariate model, as the restriction becomes more conservative (the probability of toxicity is constrained to be smaller), the expected loss becomes larger and early stopping may occur. Non-sequential designs are also found and examined using D and A criteria for optimal design. The expected loss is computed to evaluate the designs and to compare with sequential strategies. From the simulation results, it shows that using sequential design strategies does improve the performance of the design compared to using non-sequential strategies, and the improvement may be large.

<p>Background: Tougher demands from regulators on drugs efficiency and safety,governmental cost cutting and more complex areas of research, has led to that the importance of the pharmaceutical industry’s research pipelines are increasing. Even though the capital markets views on the pharmaceutical industry and its valuation is changing, the authors is not aware of any prior research that has been conducted on the topic of how the market reacts to clinical trial results or how security analysts valuates product pipelines.</p><p>Aim: This thesis aims to explain how security analysts valuate research pipelines and analyze whether the publication of clinical trial results significantly affects the pricing of multinational pharmaceutical companies.</p><p>Methodology: Three econometric models using an aggregate daily data sample of 27 years for five of the world’s largest pharmaceutical firms distinguish the price effects related to the publication of clinical trial results. Three interviews with security analysts map how security analysts value pharmaceutical research.</p><p>Results: Security analysts’ uses a combination of DCF and relative valuation when analyzing pharmaceutical firms. All interviewed analysts uses a risk adjusted net present value approach which is closely linked to the DCF approach, however, financial theory suggests that pipelines should be valuated with contingent claim models Analysts recognize that all compounds in Phase III and some Phase II projects has a impact on firm value. Clinical trials have a significant short-term impact on firm value. Phase III projects shows significant share price influence whilst early stage clinical trials do not, which shows that analysts are correct in focusing their valuation to later stage clinical trials. However, not all areas of therapy have a significant impact on firm value. Oncology is the only area of therapy where successes raises firm value, whilst failures in oncology and cardiovascular/gastrointestinal significantly lower firm value. Negative news about the research portfolio also tends to have a larger impact than positive news.</p>

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (p. 148-153).

I argue for two main theses that are at odds with the positions of many clinical researchers and philosophers who write on the ethics of clinical research. The first is that certain types of clinical trials, namely, randomized clinical trials with double or triple blinding and a placebo group are generally necessary to establish that a medical intervention is effective in treating a certain type of disease or disorder. The second main thesis is that such trials are generally not ethically impermissible. My minimalist defense of clinical trials differs from most defenses of clinical trials found in the literature. I feel that the ethical permissibility of clinical trials can be judged by answering yes to the following questions: 1) Is the potential experimental subject competent to exercise his autonomy and his right of self determination in order to enroll in the clinical trial? 2) Is the potential experimental subject informed about the nature of risk and benefit involved in his participation in the clinical trial? 3) Is the trial scientifically/ epistemically valid? 4) Will the trial attempt to answer a scientific question or questions of value? I argue that competent persons have the right to enroll in scientifically valid clinical trials so long as they are informed and consent to participate.