The United States has a long history of human medical experimentation. As early as 1900, an American doctorconducting research in the Philippines was found guilty of infecting prisoners with the Plague and Beriberi.1 Suchincidents have outraged and shocked many Americans, but they have continued to occur nevertheless. There havebeen some interesting developments in human medical experimentation this century, most of them referring to theidea of informed consent, which has its roots in the Nuremberg Code.In response to the atrocities Nazi doctors and medical scientists had committed on prisoners in concentrationcamps, a series of international and national statutes were implemented to prevent further inhuman experiments.The most renowned statute created was the Nuremberg Code, established by a three-judge panel of U. S. judges,who tried and convicted the Nazi doctors and scientists who had subjected Jewish prisoners to cruel, inhuman, andnonconsensual experiments. Developed as a legal guideline of what was acceptable in international researchstandards, the Nuremberg Code sought to govern medical studies performed on human beings by providing ethicalregulations for human experimentation based on informed consent.Despite regulations providing protection for the welfare of human subjects, inhuman atrocities affectingdisadvantaged groups persisted in the United States. For example, the U.S. government still managed to conductstudies like the infamous Tuskegee Experiment, subjecting hundreds of lower-class African-American men tosyphilis so that researchers could study and chart the natural progression of the disease. After being the mainadvocates and initiators of codes to prevent cruel experiments from being performed on human subjects, thegovernment still exposed disadvantaged groups to inhuman research and experiments without getting their informedconsent.After Allied forces defeated the Nazis and other Axis powers, the Charter of the International Military Tribunalwas drawn up and Control Council Law No. 10 was established as a uniform legal basis in Germany for theprosecution of war criminals. Control Council Law No. 10 was signed on December 20, 1945 and established thearticles for the punishment of persons guilty of war crimes, crimes against peace, and crimes against humanity.Executive Order 9547, signed by President Harry S. Truman, provided for the representation of the United Statesin preparing and prosecuting charges of atrocities and war crimes against the leaders of the Axis powers and theiragents and accessories 2. Afterwards, the military government in the U.S. zone of Germany began setting out theorganization and powers of certain military tribunals. The infamous Nuremberg trial was one such tribunal. It wasdesignated officially as the United States of America v. Karl Brandt and Case No. 1 of Military Tribunal I.Military Tribunal I was constituted on October 25, 1946, and immediately dove into the prosecution of 23 Germanphysicians and scientists associated with the Nazi party who were accused of inflicting a range of vile and lethalprocedures on vulnerable populations and inmates of concentration camps between 1933-1945.3The Medical Case began a few months after 19 of 24 leaders of the Third Reich were found guilty of accusationsof war crimes.4 Twelve of the nineteen leaders were sentenced to death, and the others were imprisoned forvariable terms. At first, American military forces occupying Germany had not planned to conduct an inquest onhuman experimentation, but they changed their minds as information emerged about the medical atrocitiescommitted in concentration camps. Shocked by the information that they received, American forces decided topursue the matter as a war crime under the Charter of the International Tribunal.5On December 9, 1946, the twenty-three physicians and scientists were put on trial for participating in AdolphHitler's racial cleansing movement. In his opening statement, the chief prosecutor Telford Taylor claimed that themedical practitioners were on trial for murders, tortures, and other atrocities committed in the name of medicalscience.6 Many doctors were involved in the Nazis racial hygiene policies, and half of the German doctors wereNazi Party members. Those medical physicians and scientists who were not members of the Nazi Party had to bewell connected with the Nazi political hierarchy. Nazis believed that doctors had a special role in improving theGerman race; after all, the medical and science profession played a key role in developing and testing Nazi racialhygiene theories.At the end of the 19th century, German Social Darwinists, fearing a general degeneration of the human race, setabout to establish a racial hygiene that would combat the disproportionate breeding of inferiors, the celibacy of theupper classes, and the threat posed by feminists to the reproductive performance of the family.7 Anti-Semitism didnot play a major role in early racial hygiene theories as it did when the Nazi Party started to rise. The mastermindsof the theory, Alfred Ploetz and Wilhelm Schallmayer, were more concerned about the indiscriminate use of birthcontrol by "the fit" and the provision of inexpensive medical care to "the unfit", than the breeding of superior raceswith inferior races. In fact, Ploetz classified Jews, along with Nordics, as being one of the superior, cultured racesof the world.8 But that attitude toward Jews had begun to change toward the 1920s and the rise of Nazism. In1918, racial hygiene was identified as a political program that stands above all parties by the racial hygienistHerman W. Siemens. Siemens argued that racial hygiene was based on the facts of inheritance and variability."Inheritance" meant that man owed the essential part of his character, good or bad, physical or spiritual, to hisgenetic material, and "variability" implied that men differed substantially in their genetic value resulting in men whowere genetically classified as fit or unfit.9 He claimed that if men who were fit bred less than those who wereinferior, the quality of the race would decline. Siemens argued that the goal of a positive racial hygiene was toensure that the fit left more offspring than the unfit, and if this failed, Germany would collapse in the face of anAsiatic triumph.10This philosophy evolved more in the mid-1920s as the Nazi Party came to power and included in its tactics anti-Semitism, especially when the right-wing faction of the racial hygiene movement merged with National Socialism.The conservative, anti-Semitic J.F. Lehmann Verlag took over the publication of the main racial hygiene journalshortly after World War I and set the stage for Nazi ideologues to incorporate eugenic rhetoric into theirpropaganda.11 Biology played an important role in Nazi ideology. In 1929, a number of physicians joined theNational Socialist Physicians League to coordinate Nazi medical policy and purify the German medical communityof Jews. By 1933, nearly 3,000 doctors joined the League before Hitler came to power, and by 1942, more than38,000 doctors (constituting about half the doctors in the country) had joined the Nazi Party.12 In fact, two majorinstitutes were established, the Kaiser Wilhelm Institute for Anthropology in Berlin and the Kaiser Wilhelm Institutefor Genealogy in Munich which recognized racial hygiene as a primary research goal. Both institutes conductedresearch in the fields of criminal biology, genetic pathology, and human genetics. Both institutes also trained SSphysicians and helped construct the genetic registries later used to round up Jews and Gypsies.13 These institutesalong with other racial hygiene institutes were also conducting twin studies, studies of identical twins raised apart tosort out the relative influences of nature and nurture in human character and institutions. Racial hygienists believedthat many human behaviors, such as crime, alcoholism, wanderlust, and divorce, were at root genetic, and studiesof how twins behaved in different environments were supposed to prove the ultimate genetic origins of racial andsocial differences.14 Thus, the medical profession was essential in the Nazi platform.The Nazis adopted three main policies to begin their medical racial cleansing programs. These policies were theSterilization Law, the Nuremberg Laws, and the euthanasia operation, which led to subsequent mass killings.Drawn up by several of Germany's leading racial hygienists, on July 14, 1933, the Nazi government passed theSterilization Law permitting the forcible sterilization of anyone suffering from genetically determined illnessesincluding schizophrenia, epilepsy, Huntington's Chorea, deafness, and severe alcoholism.15 As a result of the law,about 350,000 to 400,000 people were sterilized in Germany. Sterilization and abortion were instituted forindividuals of inferior genetic stock and declared illegal and punishable in some cases by death as a crime againstthe German body for healthy German women. Birth control of all forms was prohibited, except for Jews in which itwas generally available and encouraged. Two years later, in 1935, Hitler ratified the Nuremberg Laws, excludingJews from citizenship and outlawing marriage or sexual relations between Jews and non-Jews. A further measure,the Marital Health Laws, required couples to submit to a medical examination before marriage to detect and avoidthe possibility of racial pollution. The laws were considered public health measures and were administeredprimarily by physicians.16 A month after World War II began, in October 1939, the Nazis engaged in euthanasiaoperations. Hitler decreed orders that certain doctors be commissioned to grant a mercy death to patients judgedincurably sick by medical examination. The euthanasia operation was planned and administered by leading figuresin the German medical community. The Germans forcible euthanasia operation was an economic endeavorimportant during wartime to free up beds. The first gassings of mental patients took place in Poland 45 days afterGermany invaded that country. By August 1941, in the first stage of the operation, more than 70,000 patients fromGerman mental hospitals had been killed. Afterwards, euthanasia became part of normal hospital routine inGermany itself. Handicapped infants, people requiring long-term psychiatric care and judged incurable, and elderlypatients in homes were regularly put to death.17 To the Germans, these were people whose lives were not worthliving. The euthanasia operation eventually led to the destruction and genocide of Jews, homosexuals, Communists,Gypsies, Slavs and prisoners of war.The question of what to do with Jews was cast as a public health problem to the Third Reich. In 1935, the Fuhrerof the Nationalist Socialist Physicians League, Gerhard Wagner, declared that Judaism was an incarnate disease.He claimed that various diseases, including insanity, feeblemindedness, hysteria, neuralgia, chronic rheumatism, andflat feet were more common among Jews than non-Jews18 So began one of the greatest atrocities of mankindwhen Nazis enforced extermination of Jews and other populations by gassing them in concentration camps. TheNazis used physicians and scientists to carry out their sadistic policies and exploited both the intimacy and authorityof traditional physician-patient relationship. Doctors served as executors and performed selections of people to bekilled in the concentration camps. In fact, a decree was issued in 1943 saying that only physicians trained inanthropology could perform selections at concentration camps. 19Medical professionals also used the Nazi Party for their advantage and benefit. Ambitious researchers used theracial hygiene policies to their advantage. The researchers, many of whom were members of the Nazi Party, couldavail themselves on experimental subjects without limitations and could justify and rationalize their actions by thenotion that the concentration camp inmates were eventually slated to die.20 The medical community also grewsubstantially under the Nazis, and the physicians achieved a higher status in the period of Nazism than at any timebefore or afterwards. The Office of the President at German universities was occupied by physicians 59% of thetime during the 12 years of Nazism in contrast to 36% of the time for the decade prior to Nazism and to 18% ofthe time for the decade following the Nazi period. Doctors also prospered financially, earning 2,000 RM morethan lawyers by 1936. Also, many physicians were in support of Nazi ideology and engaged in the correlationbetween Nazi ideology, social policies, and medicine. They were intrigued by the Nazis efforts to biologize ormedicalize a broad range of social problems, such as crime, homosexuality, the collapse of the German imperialstrength, and the Jewish and the Gypsy problems.21 The physicians and the scientists wanted to be among the firstto make the medical break through that would advance the military goals of the Third Reich and make them heroesof racial medicine. The Nazis, the physicians, and the scientists all held this view:There were superior and inferior races, worthies and unworthies, healthy and diseased. If itrequired the deaths of 20 or 100 Russian prisoners of war to increase the chances of saving oneGerman pilot, this was a justified investment. Concentration camp inmates were valued as slavelabor and when that labor was exhausted, they were not even worth keeping alive. They werelives without value, and their death implied a saving.The urgency of the war effort and the endorsement of the highest state authorities further encouraged physiciansand scientists to perform human subject research on problems of pressing concern on the battlefield.23During the trial of the 23 physicians and scientists, the racial hygiene view was used to justify their participation inthe vile human experimentation they conducted with concentration camp prisoners. The physicians maintained thatresearch was necessary in times of war and national emergency, military and civilian survival was dependent on thescientific and medical knowledge derived from human medical experimentation.24 The trial was held at Hitler'sPalace of Justice in Nuremberg, which was the site of Hitler's administrative and judicial offices and his stupendousmass rallies.25 The defendants, which included Karl Brandt, Hitler's personal physician, who was also ReichCommissioner for Health and Sanitation and for which the case was named, were prosecuted in a United Statesstyled military court presided by a three-judge panel consisting of Americans.For eight months, witnesses from hospitals and camps throughout Germany and Eastern Europe were brought toNuremberg to testify. Various transcripts and testimonies revealed the atrocities and heinous acts that werecommitted in the concentration camps against Jews, Gypsies, and other classes of people the Nazis viewed asinferior. Medical experiments listed under crimes committed in the guise of scientific research included mustardgas, epidemic jaundice, sterilization, typhus, incendiary bomb experiments, muscle and nerve regeneration, andbone transplantation.26 Court records described how numerous individuals died in agony and terror under the coldeye of the physicians and scientists who designed protocols and observed and recorded the manner of death. Inthe freezing experiments, Nazi researchers conducted experiments in the best way to thaw out Luftwaffe fliersforced to bail out over frigid waters of the North Sea. They tested various thawing techniques by exposing anumber of prisoners to freezing conditions and experimented with various methods of reviving them.27 Otherexperiments they conducted for military purposes included the seawater experiments in which researchers forcedsubjects to drink seawater to determine how long pilots could survive downed in the ocean and establishing thepoint at which lungs exploded due to atmospheric pressures, an important issue for fighter pilots seeking to avoidanti-aircraft fire. In the incendiary bomb experiments, experiments were conducted at concentration camps to testvarious phar Back to Table of Contents To Footnotes/Works Cited aceutical preparations on phosphorus burns. Burns were inflicted on experimental subjects withphosphorus matter taken from incendiary bombs, which caused severe pain, suffering, and serious bodily injury.28Many prisoners were also subject to inoculations of infectious disease pathogens.29 An estimated 100,000 humanbeings died horrible deaths in the course of experiments at Auschwitz, Buchenwald, Dacheau, Sachsenhausen, andother camps.30After eight months of hearing such malicious crimes and acts done by researchers regarding humanexperimentation, on August 20, 1947, the judges gave the verdict, finding 15 of the 23 defendants guilty of warcrimes and crimes against humanity, including human experimentation involving unconsenting prisoners.31 Sevenwere found not guilty and one was acquitted of the charges of having performed medical experiments but wasfound guilty of SS membership. Seven of the fifteen found guilty were sentenced to death by hanging and the othereight were imprisoned. Karl Brandt was one of the physicians sentenced to death, and on the day of his hanging,he exclaimed waiting beside the gallows, "It is no shame to stand on this scaffold. I served my fatherland as othersbefore me!"32 Even upon their deaths, a majority of the physicians and scientists claimed that they did not doanything that was wrong.The American judges at Nuremberg wanted to do more than punish the Nazi researchers for their actions.They sought to establish appropriate ethical standards for the conduct of human experimentation that would beuniversal and prevent Nazi atrocities from ever occurring again. Thus the Nuremberg Code, a set of ten principlesto provide ethics and limitations on human experimentation, was born.The Nuremberg Code was based on a convergence of historical documents, testimonies, and standards of ethicalhuman experimentation in the Doctors Trial. The principles of the Code were derived from the testimonies of twomedical expert witnesses for the prosecution, Leo Alexander and Andrew Ivy, who were heavily influenced by theoaths, codes, and writings of such great thinkers as Hippocrates. The Hippocratic Oath, written some timebetween 470 and 360 B.C.E., had been a significant ethos of medical practice and ethics and declared that thephysician should work to the best of his ability for the good of his patients. The Oath stated, "I will follow thatsystem of regimes which, according to my ability and judgment, I consider for the benefit of my patients and abstainfrom whatever is deleterious and mischievous."33 The judges had incorporated the medical experts' views into theirfinal judgement and enumerated the 10 principles of the Nuremberg Code.The Code provided guidelines for the research setting, the integrity of the investigator, the balancing of rights andbenefits, and the most important provision of all, the specifics of voluntary informed consent. In fact, the very firstprinciple of the Code declared that the voluntary consent of the human subject is absolutely essential. The firstprinciple was followed by two paragraphs which laid down the specifics of voluntary consent, stating that theperson involved in an experimentation should have the legal capacity to give consent, situated to exercise freepower of choice, given knowledge and comprehension of the experiment, and be made aware of the risks anddangers. The Nuremberg Code became the first code to establish ethical standards for human experimentation andgovern human experimentation in international law. The Code spurred on the development of other legal policies togovern human experimentation based on voluntary, uncoerced, and informed consent.34The Nuremberg Code was not a flawless document, and the judges did not consider therapeutic research orsubjects who were incompetent to make informed judgments in its implementation. The judges did not considerthe fact that terminally ill patients might become depressed or unwilling to undergo further treatment if informed oftheir prognoses. So, in 1964, the World Medical Association created the Declaration of Helsinki, which drew asharp line between therapeutic and non-therapeutic research.35 The document did not obtain an absoluterequirement that informed consent be obtained in the setting of therapeutic research and introduced the notion ofguardianship as means of obtaining consent from incompetent subjects.36 The Declaration permitted thephysicians, under certain circumstances that he or she must defend, to waive the requirement of informed consent.Nevertheless, the Nuremberg Code was supposed to serve as the ethical basis for researchers conductingexperiments on human subjects. The Nuremberg Code was supposed to be a guard against further atrocities andprovide protection for human subjects of research. One author stated:The Nuremberg Code gave us a blue print for a better world. It showed us that wanton aggression cannot bepermitted if we are to have a secure world and assured peace. The Code showed us that we must reach thebehaviors of individual to create a better world. That we must penetrate the veil of national sovereignty and punishthe individual for violations of international law if we are to give that law life and vitality. Nuremberg also taught usthat we need to recognize individuals as having international rights, which are not dependent on nation-staterecognition.37However, the United States, the main initiators of the rules to protect human research subjects and toprevent further atrocities, were the perpetrators of its own heinous acts justified in the name of medical science.After punishing Nazi researchers and establishing a universal law, the United States allowed its researchers toconduct its own racial and social hygienist experiments on minorities and other disadvantaged populations thatwould be deemed unfit in the terms of Nazi ideology.Human experimentation has remained a scientific dilemma in the medical arena. Human experimentation refers toscientific experiments, in which humans are used as subjects. The selection of human subjects for experimentscontinues to present many challenges. Subjects in the experiments can be nonconsensual or consensual.Unfortunately, many times subjects are unwilling or unknowing subjects of the experiments. Even more, the humanrights of these individuals have been almost disregarded by the physicians involved. Fifty years ago, theNuremberg Code called for the informed consent of participants in human research.38 That same year penicillinwas recognized as the standard of care for syphilis. However, researchers from the U.S. Public Health Servicecontinued to conduct a long running study in Tuskegee, Alabama, on the course of the disease in African Americanmen and chose not to provide penicillin to study participants.39 The Tuskegee study remains one of the mostcontroversial experiments that has occurred in the United States. The Tuskegee study has since become a nationalsymbol of racial and scientific exploitation.40 The fact that the government was involved in the experiment castsdoubts on the future trust of the government by African Americans, as well as distrust for the medical arena. Thefact that the study used poor African-American men at the governments consent demonstrates a substantial conflictwith the basic rights that each citizen of the United States is supposed to possess. Even more, the impact of thestudy continues to be felt as the mistrust it generated in the eyes of African Americans.The Tuskegee study began in 1932, when the federal government promised four hundred poor African Americanmen -- all residents of Macon County, Alabama -- free treatment for Bad Blood, a euphemism for syphilis, whichwas epidemic in the country at that time.41 These men signed up with the U.S. Public Health Service for freemedical care. The service was conducting a study on the effects of syphilis on the human body and, at that time,the sexually transmitted disease was rampant in Macon County, Alabama.42 The study ran from 1932-1972.Throughout the four decades, the men in the study at no point were ever told that they had syphilis. Nor, did thephysicians tell the syphilitic men that they might have infected their wives, or doomed their children to a devastatingcongenital infection.43 In fact, they were continuously told that they had bad blood and were denied access totreatment, even for years after penicillin came to use in 1947.44 Even more, the physicians conducting the studywent through extreme lengths to ensure that the men would not receive therapy from any other sources. It was notuntil the early 1970s that the popular media disclosed the research and the study was terminated.The fact that the study targeted African American men raises another dilemma. The researchers targeted apopulation to study a problem that was not confined to that group. Even more, the men that were targeted werealready disadvantaged in terms of socioeconomic status and medical condition.45 Because of the low educationalstatus of the majority of the patients, it was impossible to appeal to them from a purely scientific approach.46 Theywere vulnerable subjects who were given incentives for their participation. The incentives offered by the PublicHealth Service included: free physical examinations, free rides to and from clinics, hot meals on examination days,free treatment of minor ailments, and a guarantee that a burial stipend would be paid to their survivors.47 Theunfortunate thing is that free hot meals meant more to the men than $50 worth of free medical examination. Thematerial incentives gave the men a support and a basic feeling of good will towards the physicians. In reality, theirvulnerability was just the root of an unethical medical experiment gone bad.The issue of why the physicians did not terminate the experiment after a cure was found remains one of the mostdifficult aspects of the experiment to face. Throughout the forty years of the study, it was periodically reviewed byU.S. Health Service officials. In each case the study was extended based on the argument that stopping the study,while helping the individuals, would interfere with the benefits of medical science of studying this untreateddisease.48 Those studying the men rationalized their point of view by claiming that these extremely poor and sickmen had the perks of medical attention, free aspirin for their aches and pains, a free nurse to watch over them, andwould have their funerals paid for. These physicians ignored the fact that penicillin was a relatively inexpensive,safe, fast acting, wonder drug that cured many infections, including syphilis.49The effects of the study are limitless. Over the years, the men suffered the effects of the untreated sickness,which can cause brain damage and paralysis. Some men infected their wives, and some of them, in turn, passedthe disease on to their children.50 By the time the study was exposed in 1972, 28 men died of syphilis, 100 otherswere dead of related complications, at least 40 wives had been infected and 19 children had contracted the diseaseat birth. The U.S. Department of Health, Education, and Welfare only stopped the study after its existence wasleaked to the public and it became a political embarrassment.51The Tuskegee experiment has left a legacy of mistrust in the African American community. Louis Sullivan,MD, president of Morehouse University School of Medicine in Atlanta, explained that the Tuskegee study, morethan any other factor, resulted in the African American community's distrust of the medical arena.52 Even more, itis such abuse that has caused a significant number of African Americans impacted by HIV/AIDS to refuse servicesfrom mainstream medical professionals. This is only one of the consequences of the study. Others suggest theTuskegee study is the cause for the low participation of African Americans in clinical trials and organ donationeffort.53 In essence, the study continues to cast a long shadow over the relationship between African Americansand bio-medical professionals. Some suggest that the apology by President Clinton for the experiment will mark arenewed effort to heal the wounds. However, others are unsure that after a quarter of a century and six presidentslater, whether the apology can make change, if any.54 It is unfortunate that it took the Tuskegee incident for theU.S. medical community to learn the lessons of the Nuremberg Trials and the effects of human experimentation.The Tuskegee syphilis study has been one of the most widely cited examples of research in which human subjectswere not adequately protected. Even more, the fact that the study was government sanctioned has led to manyunfortunate consequences, including a lack of trust by African Americans towards the medical community and theU.S. government. Although the apology by President Clinton was a necessary remedy, it alone can not ensure thatan atrocity such as Tuskegee will not be duplicated. However, after the truth of the experiment was revealed,clinical research policy reforms were enacted to legally protect patients while binding science to specific rules andregulations. Although this will not take away the pain of the experiment, it will prevent others from becoming atarget of another unethical experiment (or will it?).In 1952, at the Sloan-Kettering Institute, Chester M. Southam injected live cancer cells into 396 inmates at theOhio State Prison. Half of the inmates involved were black. Oddly enough, one of the sponsors of thisexperiment, the National Institutes of Health, had also been a sponsor in the Tuskegee experiments. Southam wastemporarily stripped of his medical license after injecting 22 elderly hospital patients with cancer cells at Brooklyn'sJewish Chronic Disease Hospital.55Once again we see that at the heart of protection against unethical medical experimentation is the principle ofinformed consent. Not only is a patient insured the right to consent, but they must also be consenting with fullknowledge and understanding of what is happening. They must be aware of side effects, possibility of failure,recovery time, etc. This is no longer a simple concept that can easily be misconstrued. The key word is notconsent, but rather both informed and consent.On November 28th, 1953, in New York City, a psychotic and depressed Dr. Frank Olson threw himself out of atenth floor hotel window. Nine days earlier, Dr. Olson had been unwittingly slipped 70 mcgs of lysergic aciddiethylamide into an after-dinner drink by a colleague, Dr. Sidney Gottlieb, head of the CIA's Technical Serviceand key orchestrator in MKULTRA, to determine the effects of LSD on unknowing subjects. After ingesting 70mcgs of LSD, Dr. Olson entered a nine-day state of psychosis that culminated with him jumping through ascreened glass window to his death. In defense of his actions, Dr. Gottlieb and others in Operation MKULTRAsaid that non-consensual human experimentation with LSD was necessary to gather accurate information about thedrug's effects.56Two years later in San Francisco Captain George White of the OSS sat behind a two-way mirror, martini in hand,observing the effects that LSD has on sexual behavior for Operation Midnight Climax. Operation Midnight Climaxwas a sub-project of MKULTRA. Captain White hired prostitutes to lure unknowing patrons into a CIA-runbrothel fully equipped with surveillance cameras, audio bugs, and two-way mirrors. At these safe houses, theunknowing subjects would be given beverages laden with LSD. CIA agents would then observe the effects thatLSD and sexual intercourse have on various interrogation technique.57 The same reason given for the experimenton Dr. Olson was supplied for these actions. How can this be legal? Both of these cases of humanexperimentation without informed consent were entirely legitimized and funded by the Central Intelligence Agency.Operation MKULTRAs ultimate goal was achieving a state of mind control through drugs, electronic devices, orradiation. Unlike most other instances of non-consensual human experimentation, Operation MKULTRAtranscended race and economic class in most of its subject gathering processes.58 This pursuit for a ManchurianCandidate stretched laws dealing with the jurisdiction as designated in the National Security Act of 1947 thatestablished the CIA in addition to the infringement of basic human rights.The infringement of human rights laws and various laws dealing with non-consensual human experimentation wasjustified by the CIA through the rationale that experimentation of individuals with out consent was necessary tocollect accurate results. In a 1954 memo, then CIA Director, Richard Helms justifies this by stating: "Most of ourdifficulty stems from the fact that the individuals subjected to testing must be unwitting... In the circumstances ofpotential operational use of this technique, it is virtually certain that the target will be unwitting".59Those accurate results would then be applied towards research with purpose of insuring national security. Thisrationale proved inconsequential when the operation was exposed through a number of Senate hearings in the1970's. The Kennedy Hearing of 1977 actually began the process towards Executive Order 12333 that prohibitsthe experimentation on humans without consent by intelligence agencies.Operation MKULTRA was initiated on April 13, 1953. It was the next step of a smaller operation calledBLUEBIRD that was spawned by a response to rumors that the Chinese and Soviets were far ahead of the U.S. inresearch dealing with mind control. According to the few documents on the operation that were not destroyed byorder of CIA director Richard Helms in 1973, MKULTRA was an umbrella project that contracted 149 sub-projects to various universities. According to Admiral Stansfield Turner, Director of Central Intelligence, 19 sub-projects involved the drugging of human subjects without informed consent.60Only top officials knew the exact purpose of MKULTRA. Most of the doctors involved were only aware of theparticular sub-projects allocated to them from operatives. Some of these officials found themselves to be unwittingguinea pigs. It was common practice amongst the upper echelon officials within the project to slip each otherdoses of various drugs, LSD being the most prevalent, to see the effects that it has on subjects not knowing thatthey have been drugged. After initial experiments, Dr. Gottleib, the man responsible for the death of Dr. Olson,concluded that while it has little use as an interrogation drug, LSD could be used on leaders to create publichumiliation. They even began planning an attempt to slip Fidel Castro, dictator of Cuba, LSD to decrease hismachismo image.61After discovering the files on MKULTRA that were not destroyed in 1973, the more friendly CIA administrationheaded by Admiral Stansfield Turner handed them over to Congress in 1975. The struggle to obtain these fileswas primarily won through the usage of Freedom of Information Act. The Freedom of Information Act, passed in1966, allows private entities more access to information about government activities.62 Two years later, a specialhearing by Senator Edward Kennedy took place that examined the Operation MKULTRA and its violations of theCIA jurisdiction guidelines within the National Security Act of 1947. During the hearing, it was revealed that theabove stories were true in addition to many other violations of already established informed consent laws.Informed consent, as used in the hearing, can be defined as full processes of disclosure, comprehension, andvoluntary agreement to participate.63Citing the National Security Act, Dr. Gottlieb refused to inform the hearing of information not otherwise provided inthe remaining files on MKULTRA. When confronted about various cases of human experimentation withoutinformed consent, Dr. Gottlieb and other CIA operatives working on MKULTRA stated that the utilization ofunwitting subjects was necessary. The rationale for such testing was "that testing of materials under acceptedscientific procedures fails to disclose the full pattern of reactions and attributions that may occur in operationalsituations".64 They stated that the gathering of such data, and its strict secrecy from all but top CIA officials, wascrucial to national security, and therefore protected under the National Security Act of 1947.As a result of the Kennedy Hearing of 1977, then President Carter began the process of drafting legislation directlyprohibiting such abuses of human rights through non-consensual experimentation for the purpose of gatheringintelligence information. The attempt to narrow the potential for future abuse from the intelligence community wasfinalized by President Reagan's Executive Order 123333. Among other items listed that streamline intelligencejurisdiction, the order states:No agency within the Intelligence Community shall sponsor, contract for or conduct research onhuman subjects except in accordance with guidelines issued by the Department of Health andHuman Services. The subject's informed consent shall be documented as required by thoseguidelines. 65It is true that Operation MKULTRA took place. Dr. Olson did jump out of a ten-story window to his death dueto a drug-induced psychosis initiated without consent by the CIA. Prostitutes on CIA payrolls did lure unknowingbar patrons to CIA funded brothels where they were slipped LSD and observed while having sexual intercourse.At the time, both activities were arguably legal due to the fact that the information gathered was supposedly crucialto national security because of its relevance to research in mind control. However, once information aboutMKULTRA went public, hearings commenced and Executive Order 123333 was passed prohibiting, in theory,human experimentation without informed consent by an intelligence agency for any reason.In 1970, it was made evident that men were not the only people at risk of medical experimentation. Children tooare very susceptible to mistreatment. The main reason for children being at risk of experimentation is their inabilityto consent for themselves. Adults must give consent for children, but they can be misled, as was the case at a freechild-care program at Johns Hopkins University.Over 7,000 young boys were used in an experimental three-year study that could have labeled them as criminalsindefinitely. The majority of these boys came from poor, African American families. These experiments were onceagain funded by the National Institute of Health, and were supposed to test for anemia and other medicalproblems. However, in actuality, the blood was screened for the extra Y chromosome. Such screening enabledthose boys who were XYY to be labeled as at risk criminals. It was believed at the time that XYY boys weremore aggressive and at risk of becoming criminals.Similar experiments were conducted on 6,000 young men in institutions for abandoned children. Once again themajority of these boys were African American. When parents were involved, their permission to conduct tests wasoften coerced. The project director, Digamber Borganokar, was not a physician, and his assistants were merelyundergraduate psychology majors. Despite certain allegations, Johns Hopkins University had never grantedpermission for the experiments. Laws protecting people against such incidents were already in effect, but had donenothing to prevent such experiments.66In Philadelphia, Doris Jackson had the opportunity to tell CBS America Tonight that she had been refused the rightto see her son after his death, and when she finally did, she discovered that his brain had been removed. Thisoccurred in 1987. Pennsylvania had a doctrine of implied consent. This basically stated that unless a patient orsubject has signed a written document saying the contrary, then consent has been implied. Unfortunately, fewpeople were aware of the law and felt they were denied the right to object. Researchers claimed that the organsthese families donated went towards research, however, that was not always the case. More often than noted,these organs were going towards building the resume of students not because there was a need for the study, butrather because the students involved wanted self-gain.67 Implied Consent has opened up an entirely new argumentfor the precedent set by the Nuremberg Code. Can implied consent be informed consent?Throughout the last few decades, there have been multiple experiments carried out by the United States Military.The Navy was responsible for spraying bacteria over San Francisco, under the claim that the bacteria washarmless and was merely a simulated attack. However, many San Francisco residents became ill. The U.S.military also allegedly released harmless gasses over six U.S. and Canadian cities once again under the cover up ofstudying a simulated attack. These harmless gasses, however, resulted in respiratory problems for many non-consenting civilians. Twelve people died when Tampa Bay, Florida experienced a sharp rise in Whooping Coughcases after a CIA test.68In 1985, the courts ruled against a military liability case, reasoning that by doing so they would affect the chain ofcommand. A former U.S. Army sergeant attempted to bring a lawsuit against the Army for using drugs on him,without his knowledge, in United States v. Stanley, 483 U.S. 669 (1987). Justice Antonin Scalia wrote thedecision in this case, which absolved the U.S. military from any liability in cases where the military might conductmedical experiments without informed consent. It also had the effect of absolving all past wrong doings as well.Conservative Justice, Sandra Day O'Connor, who dissented, had cited principles of human rights, and conceptsformulated under the Nuremberg Code in an attempt to hold military commanders responsible for their deeds.69The Gulf War Syndrome was thought to be a direct result of the Gulf War. The Gulf War Syndrome is a title thathas been given to a wide array of symptoms ranging from mere skin diseases to attacks on the nervous system.1.7 million soldiers were sent to the Persian Gulf in 1990. Twenty-two percent of these soldiers were AfricanAmerican. It is widely believed that the Gulf War syndrome stems partially if not entirely from the experimentalvaccines given to U.S. soldiers. Soldiers were forced to take these vaccines under federal law but were orderedto deny the fact that the vaccines were indeed experimental. Soldiers have had dishonorable discharges from themilitary for refusing to take the vaccines. The media has focused on the possibility of the syndrome stemming fromexposure to chemical weapons; however, 33% of soldiers infected with the Gulf War Syndrome had never left theUnited States.70In conclusion, human medical experimentation still remains a dilemma in the United States. Legal developments toprotect citizens from experimentation without informed consent have been ineffective. The Nuremberg Code,which set the precedent for obtaining informed consent, was not able to keep human experimentation withoutinformed consent from occurring, especially when the experiments targeted minorities and disadvantagedpopulations. These experiments were able to continue and occur because the United States held the same racialhygienists views as the Nazis concerning people that were fit and unfit.After establishing the Code, the U.S. entered into the Cold War hysteria, competing against Russian and ChineseCommunists. Government officials, scientists, and doctors worked vigorously in trying to surpass the achievementsand accomplishments of the Communist countries to prove, in ways similar to the Nazis' actions, that a Democracywas the quintessential form of government and that the United States was the best country in the world. Alreadyplagued by a history of racism and a history of prejudice toward the poor, the United States continued and beganto conduct experiments on people they deemed to be unfit to place the U.S. in spot #1 of the Cold Warcompetition and to improve the livelihood of the dominant culture. To Americans, as evident by the experimentsconducted after Nuremberg, African-Americans, poor people, soldiers, the under class, like alcoholics, and otherdisadvantaged populations were considered to be lives worth not living if it meant advancing and saving the lives ofthe dominant, advantaged, white, and superior cultures. Many government officials and agencies and medicalassociations were able to continue to perform these experiments because they took advantage of populations whodid not have a political voice and little knowledge of policies promoting protection for their general welfare. Theseagencies and associations also deceived many participants and rationalized many of their actions by saying that theywere promoting national security. Since the passage of the Nuremberg Code, American society has been plaguedby human experimentation incidents such as the incident that occurred in Tuskegee.The Tuskegee Syphilis Study began in 1932, years before the adoption of the Nuremberg Code. However, thestudy continued until 1972, which was well after the Nuremberg Code was created. Even more, the studycontinued even after penicillin was discovered as a cure for syphilis. As the awareness of the benefits of penicillingrew, the researchers saw a greater urgency in continuing "a-never-again-to-be-repeated-opportunity."71 Yet,doctors claimed that they were merely doing their jobs. John Heller, MD, then director of the Public HealthServices of Venereal Diseases stated, "For the most part, doctors and civil servants simply did their jobs. Somemerely 'followed orders', others worked for 'the glory of science'". However, was this really the case? To denythat race played a role in the Tuskegee Study is naive. All 600 subjects (399 experimentals and 201 controls)were black; the Public Health Service directors and most of the doctors were white.73In essence, the Tuskegee Study was simply an unethical and immoral experiment on disadvantaged subjects. Evenmore, it was a premeditated genocide on a disadvantaged group, who was simply uninformed of what theirparticipation really consisted of. The Tuskegee Study represents the misfortune of human experimentation thattargets disadvantaged or vulnerable groups. Unfortunately, race played an important part of the disadvantage forthese subjects. Human experimentation of this kind should have never been allowed to occur. However, if theNuremberg Code could not prevent it, what could have?Given the atrocities committed on unknowing subjects during project MKULTRA, the CIA, in addition to otherintelligence groups, had almost as much freedom as the Nuremberg doctors when it came to humanexperimentation. The CIA legitimized their actions under MKULTRA by explaining that the results of theexperiments were detrimental to national security, thus being entirely legal according to their 1947 charter. Whenthe United States Congress learned about the horrors committed under Project MKULTRA during the 1977Kennedy Hearings, the process towards Executive Order 123333 began. This order made it illegal for allintelligence agencies to practice experimentation on unknowing subjects.However, most current medical experiments performed on humans have involved the military, which has free reignto do as it wishes because of the precedent set by the Supreme Court decision in 1985. Throughout the 1980sand early 1990s, there were a number of incidents in which the U.S. military was allegedly involved in conductingexperiments on American citizens and soldiers, including the Gulf War Syndrome.Presently, fewer experiments are being carried out because the concept of informed consent is beginning to beaccepted. Informed consent is now recognized by more government agencies and medical associations than in thepast. There have been current developments in the sphere of medical experimentation, such as a development thatcame with a case concerning the studies at Johns Hopkins University, stating that parents are legally responsible forchildren under 18 and must therefore be the persons giving informed consent when children are involved in medicalexperiments. There have also been developments in the military involving the Gulf War Syndrome. Perhaps, thecurrent crisis concerning he Gulf War Syndrome will demand results and progress in the realm of monitoring andcontrolling human medical experimentation. There has been a decrease in the number of human medicalexperiments performed without informed consent. Hopefully, the next set of developments will put morereasonable controls on the military.
Clinical trials a career final
Clinical Trials: A Story, A Science, A Career Presented at GFSU on July 30, 2012 Dr. Bhaswat S. ChakrabortySr. VP & Chair, Science Core Committee, R&D Cadila Pharmaceuticals Ltd.
The Nazi Medical War Crimes• “Medical experiments” were performed on thousands of concentration camp prisoners• Included deadly studies and tortures such as injecting people with gasoline and live viruses, immersing people in ice water, and forcing people to ingest poisons
War Crimes Tribunal at Nuremberg• Indictments: – Conspiracy to commit crimes against peace – Planning, initiating and waging wars of aggression – War-Crimes – Crimes against humanity
In his closing remarks Robert Jackson, the U.S. Chief Prosecutor issued the followingwarning: “….. If we cannot eliminate the causes and prevent the repetition of thesebarbaric events, it is not an irresponsible prophecy to say that this twentieth centurymay yet succeed in bringing the doom of civilization”
The Nuremberg Trial• December 1946 – 23 physicians and administrators – for their willing participation in the systematic torture, mutilation, and killing of prisoners in experiments – Despite the arguments of the German physicians that the experiments were medically justified, the Nuremberg Military Tribunals condemned the experiments as “crimes against humanity” – 16 were found guilty and imprisoned – 7 were sentenced to death• August 1947 verdict – A section called “Permissible Medical Experiments.” This section became known as the Nuremberg Code
Directives for Human Experimentation NUREMBERG CODE1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legalcapacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of anyelement of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should havesufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make anunderstanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by theexperimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method andmeans by which it is to be conducted; all inconveniences and hazards reasonable to be expected; and the effects upon his healthor person which may possibly come from his participation in the experiment.The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs orengages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or meansof study, and not random and unnecessary in nature. 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the naturalhistory of the disease or other problem under study that the anticipated results will justify the performance of the experiment. 4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. 5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur;except, perhaps, in those experiments where the experimental physicians also serve as subjects.
Directives for Human Experimentation NUREMBERG CODE6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of theproblem to be solved by the experiment. 7. Proper preparations should be made and adequate facilities provided to protect the experimental subject againsteven remote possibilities of injury, disability, or death. 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and careshould be required through all stages of the experiment of those who conduct or engage in the experiment. 9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if hehas reached the physical or mental state where continuation of the experiment seems to him to be impossible. 10. During the course of the experiment the scientist in charge must beprepared to terminate the experiment at any stage, if he has probable causeto believe, in the exercise of the good faith, superior skill and carefuljudgment required of him that a continuation of the experiment is likely toresult in injury, disability, or death to the experimental subject._____________________Reprinted from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2, pp. 181-182..Washington, D.C.: U.S. Government Printing Office, 1949.
The Tuskegee Syphilis Study• 1932-72, More than 400 black men with syphilis & about 200 men without syphilis – recruited without informed consent – misinformed that some of the procedures (e.g., spinal taps) were actually “special free treatment”• 1940s, Penicillin found to be effective in syphilis – the study continued, however, and the men were neither informed nor treated with the antibiotic• 1972, Congress established regulation for human research• 1997, President Clinton apologized
Jewish Chronic Disease Hospital Study• 1963, New York Citys Jewish Chronic Disease Hospital – studies to develop information on the nature of the human transplant rejection process – involved the injection of live cancer cells into patients who were hospitalized with various chronic debilitating diseases• Researchers said that consent had been given orally, but was not documented – felt that documentation was unnecessary – because much more dangerous medical procedures are undertaken without the use of consent forms – would frighten the patients unnecessarily – good cause• Researchers were found guilty of fraud, deceit and unprofessional conduct
Positive Stories in Drug Discovery & Clinical Trials
Dr. Upendranath Brahmachari, 1920’s; Dr. Y. Subbarao, 1940’s;Discovery of ureastibamine Discovery of the role of(antimonial compound for treatment of Phosphocreatine and ATP in muscularkala azar) activity Synthesis of Folic Acid Synthesis of Methotrexate Discovery of Diethylcarbamazine
Sir Alexander Fleming, 1950’s; Penicillin Sir James W. Black, 1960’s; PropranololDr. Jerome Horwitz, 1960’s; Zidovudine Dr. Akira Endo, 1970’s; Mevastatin
Global Pharmaceutical Market• The global pharmaceutical market research has been done by many companies – All indicate a significant growth of pharma market in 2010-2011. – The forecasting indicates pharmaceutical market growth of about 4 - 6% in 2010-2011. – >$850 Billion – Expected to grow at a 4 - 7% compound annual growth rate (CAGR) through 2013. – >$975 billion by 2013
Global Top 20 Pharmaceutical Companies Revenue in $Rank Company Million(2010)01 Johnson & Johnson 61,89702 Pfizer 50,00903 Abbott 30,76404 Merck & Co. 27,42805 Eli Lilly & Co. 21,83606 Bristol-Myers Squibb 21,63407 Amgen 14,64208 Gilead Sciences 7,01109 Mylan 5,09310 Genzyme 4,516
Indian Pharmaceutical Market• 3rd largest (after US and European) generic market in volume, 14th in value – India currently holds only ~2% share, but it has been growing at approximately 10% per year – India is a leader in generic drugs and active pharmaceutical ingredients (API) – Now seeking to become a major player in outsourced clinical research as well as contract manufacturing and research – There are ~100 U.S. FDA-approved manufacturing facilities in India, more than in any other country outside the U.S – In 2010, almost 30% of all Abbreviated New Drug Applications (ANDA) to the FDA have been filed by Indian companies – India’s share of the global generics market is ~33% now
Top 10 Pharmaceuticals in India, as of 2010 Revenue 2010 Revenue 2010Rank Company (Rs crore) (Rs billion) 1 Cipla 4,198.96 41.989 Ranbaxy (Taken over by 2 4,162.25 41.622 Daiichi Sankyo in 2008) 3 Dr. Reddys Laboratories 3,763.72 37.637 4 Sun Pharmaceutical 2,463.59 24.635 5 Lupin Ltd 2,215.52 22.15 6 Aurobindo Pharma 2,081.19 20.801 GlaxoSmithKline 7 1,773.41 17.734 Pharmaceuticals Ltd 8 Cadila Healthcare 1,613 16.13 9 Aventis Pharma Limited 983.80 9.838 10 Ipca Laboratories 980.44 9.8044
Growth in Indian Domestic Market Revenue in US$ Billion
Clinical Research• Clinical research is a branch of medical science that determines the safety and effectiveness of – Medications – Medical devices (including surgicals) – Diagnostic products and treatment regimens intended for human use.• These may be used for prevention, treatment, diagnosis or for relieving symptoms of a disease• Ethical research, overseen and regulated by local and other pertinent Government authorities• Regulators and Ethics committees review the research prior to conduct as well as after completion of a study• Clinical research is often understood by four phases of Clinical Trials (Phase I – IV)
Global Clinical Research Environment Today• Large, multinational clinical trials preferred over smaller, locally- sponsored trials – Pressures on pharmaceutical and biotech companies – Budget and resource constraints• The goal is to increase access to treatment of naïve subjects by enlisting sites outside of major markets, and to drive cost savings through economies of scale.• After a steep learning curve in the 1990’s, now reaping benefits of large, multinational studies while minimizing the problems: – Hardware and IT infrastructure harmony – Support in multiple languages – Responding to regulators’ queries from several countries arriving at the same time• Better & successful management of large, multinational clinical studies
Largest Registry of Clinical Trials• ClinicalTrials.gov (www.clinicaltrials.gov) is a registry and results database of federally and privately supported clinical trials conducted in the United States and around the world. – currently contains 113,598 trials – sponsored by the National Institutes of Health, other federal agencies, and private industry – Studies listed in the database are conducted in 176 countries – 24 categories of diseases – gives you information about a trials purpose, who may participate, locations, and contact phone numbers – receives over 50 million page views per month 65,000 visitors daily
What is a Clinical Trial (CT)?• Biomedical or health-related research studies in human beings that follow a pre-defined protocol• Clinical Trials mean both interventional and observational types of studies – Interventional studies are those in which the research subjects are assigned by the investigator to a treatment or other intervention, and their outcomes are measured – Observational studies are those in which individuals are observed and their outcomes are measured by the investigators
Different Types of CTs• Treatment trials test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy• Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vaccines, vitamins, minerals, or lifestyle changes• Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition• Screening trials test the best way to detect certain diseases or health conditions• Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.
Different Phases of CT• Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions: – In Phase I trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. – In Phase II trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. – In Phase III trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely. – In Phase IV trials, post marketing studies delineate additional information including the drugs risks, benefits, and optimal use.
Participation in Clinical Trials• Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments before they are widely available, and help others by contributing to medical research• All clinical trials have guidelines about who can participate – Inclusion/exclusion criteria – The factors that allow someone to participate in a clinical trial are called "inclusion criteria" – Those disallow someone from participating are called "exclusion criteria“ – These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions – A participant must qualify for the study by I/E – Some studies need patients with illnesses, while others need healthy participants – I/E not used to reject people personally
What are the Benefits & Risks of Participating in a Clinical Trial?• Benefits – Clinical trials that are well-designed and well-executed are the best approach for eligible participants to play an active role in their own health care – Gain access to new research treatments before they are widely available – Obtain expert medical care at leading health care facilities during the trial – Help others by contributing to medical research.• Risks – There are risks to clinical trials. There may be unpleasant, serious or even life-threatening side effects to experimental treatment – The experimental treatment may not be effective for the participant – The protocol may require more of their time and attention than would a non-protocol treatment, including trips to the study site, more treatments, hospital stays or complex dosage requirements
What Happens During a CT?• Depends on the kind of trial being conducted – The clinical trial team includes doctors and nurses as well as social workers and other health care professionals – They check the health of the participant at the beginning of the trial, give specific instructions for participating in the trial – They also monitor the participant carefully during the trial, and stay in touch after the trial is completed – Some CTs involve more tests and doctor visits than the participant would normally have for an illness or condition – For all types of CTs, the participant works with a research team – A CT is most successful when the protocol is carefully followed and there is frequent contact with the research staff
The Rise of Trial Outsourcing % of PIs in a Country/Region United Western States Europe Rest of world1997 86% 9% 5%1999 80% 9% 12%2001 77% 10% 13%2003 70% 11% 19%2005 62% 13% 25%2007 57% 14% 29% •Source: Tufts Center for the Study of Drug Development analysis of FDA data
Multi-centric CTs in India• India is said to participate in 7% of global Phase III and 3.2% of Phase II trials.• 2.5% of global market.• Today, most of the big pharmaceutical companies are conducting multi-centric trials in India• All leading global CROs have also set up services in India• India has about 30 established major international CROs and nearly 100 CROs of reasonable size that are currently involved in conducting clinical trials in the country.
Opportunities forCapacity (Continuous) Development
Ethics Capacity• Ethics Committees, ethical guidelines and norms, and IRBs ensure compliance with established ethical guidelines and good practices.• Ethics committees need data to evaluate ethical conduct of a study.• Critical issues: conflict of interest, cultural specificities in obtaining informed consent from vulnerable population, safety etc.• Meaningful trials• Subject’s independent decision• Punitive measures and/or legal liability• Training of ethics committee members, accreditation of these committees and the development of stringent guideline.
GXP, Quality & Limiting Liability• There is uncoordinated effort in capacity building in clinical trials with little quality control.• More regulatory capacity to evaluate NDAs with regard to GCP and more trained principal investigators are needed.• There is also a need for more GLP laboratories, a pharmacovigilance programme and the ability to monitor sites for GCP compliance.• Mandatory provision of insurance for subjects of trials is another matter that needs to be urgently addressed involving insurance providers with provision for dispute resolution.
Regulatory Capacity• Currently a portion of the required capacity is existing but slow• Main focus: regulatory capacity of monitoring, oversight, enforcement , review and approval of trials• An innovative structure with “consultants” may be more is being sought out• A definition of conflict of interest in the Indian context for these consultants is also being looked into• Complemented by required legislative changes• Credible CROs for the conduct of need based trials• Certification for principal investigators
Expertise• Development of world-class expertise is an outcome of this growth in clinical trials • involves knowledge transfer from abroad and local expertise building• Quality control and joint trials with reputed global players• Partnerships between public and private sector and with international organizations• Guidelines and standards of learning• Human and other resource planning for clinical trials of the future (e.g., biotech therapies, molecular diagnostics and molecular epidemiology)
Data Management Capacity• Case report forms (CRFs) design• Database design• Database programming• 21 CFR part 11 compliant validation process• Loading, reconciliation and integration of external data• Medical coding• Status reporting• Forms management• Data entry and cleaning• Data locking• Statistical analysis• Report generation
Data Capture (1) CRF Manual data Electronic data No Raw data to be combined? (Manual) Yes Electronic data Get approval Raw data A
Data Capture (2) A Real time query No Are the queries answered? Approval required Yes Repeat NoData cleaning Observation/ Can this data be locked?1. Detecting & diagnosing errors Omission2. Editing incorrect data3. Integrated data passage Yes4. Outlier determination5. Robust estimation of analytical parameters Clean data Locked data B
Data Capture (3) B Locked Clean Data No Data Summary, Statistical analysis Charts/Graphs required? Yes SAS Data Sets Statistical Data Analysis Tests of Hypotheses Cohort Analyses Report Results
Data Model Courtesy Barry Williams http://www.databaseanswers.org
Pharmacovigilance Capacity: Current• aims the adverse drug reactions National Pharmacovigilance (PV) program monitors (ADRs)of medicines in order to identify previously unexpected adverse drug reactions or indicate that certain reactions occur more commonly than previously believed.• This will include the collation, review and evaluation of all spontaneous ADR reports received by the unit on a nation-wide basis.• These reports shall also be submitted to the WHO International Drug Monitoring Program for international collaboration on drug safety.• Review Periodic Safety Update Reports (PSURs) submitted by pharmaceutical companies. Pharmaceutical companies are required to submit the PSURs of all new chemicals drugs. PSURs shall be expected to be submitted every 6 monthly for the first 2 years of marketing in India, and annually for the subsequent 2 years.• Maintain contacts with international regulatory bodies working in pharmacovigilance and exchange information on drug safety.• Assess the regulatory information relating to safety in order to determine what action, if necessary, needs to be taken to improve safe use. Based on the available data, the Advisory Committee shall make recommendations on product label amendments, product withdrawals and suspension.• Provide information to end-users through adverse drug reaction news bulletins, drug alerts and seminars.
Trial Registry Capacity• The WHO had suggested a structure of the registry with a minimum required data set to be followed by all countries. The Indian Registry (CTRI) is trying to achieve that.• From November 2008 onwards, DCGI has made it mandatory to register CTs the CTRI before initiation of the study. After the implementation of this move, a significant gain in momentum of trial registration has been observed.• The CTRI performs quality assurance on submitted entries, and has a mechanism for obtaining updated data and as well as performs deduplication of submitted trials. Deduplication is the process of identifying and removing duplicate sets of data belonging to the same trial.• The Indian trial registration data set and the process of trial registration has been discussed in detail elsewhere10. In addition, guidelines are being notified by the DCGI to make contract research organizations (CROs) registration mandatory resulting in quality clinical trials.• Another important milestone for the CTRI is that since December 2008, trials registered in the CTRI are also searchable from the WHO’s global search portal, the ICTRP.• CTRI is a meaningful step towards greater transparency and accountability in clinical trials and their scientific process. An Indian registry, with the minimum data set and requirements suggested by WHO, needs to be implemented.
CT Professional Personnel• Principal & co-investigators• Clinical (medical ) investigators• Regulatory and Ethics Submissions / Feasibility Specialists• Clinical Trial Assistant (CTA) / Clinical Trial Coordinator (CTC)• Clinical Research Associates (CRA) – from entry level trainee to senior level jobs• Clinical Project Manager (CPM), Clinical Study Managers, Clinical Trial Managers (CTM)• Clinical Contract Associate / Manager• Clinical Operations Managers• Clinical Research Scientist, Clinical Research Manager• Clinical Program Managers• Clinical Associate Director, Clinical Directors• Bioanalysts• Biostatisticians• Trial Managers• Top management• ……..
Concluding Remarks• CT is a Huge Industry approaching 20 Bn USD• Ousourcing is the trend• India has terrific attractiveness as the outsourcing destination• Several areas for capacity building and expertise building• Team players are required• International Multicentre RCTs are increasing• Welcome to a career of Clinical Trialist