Re-aligning the Trust: Background Information
AAPP Annual Meeting, Nov. 4th, 1:30 – 3PM & 3:30 – 5PM

30 minute presentation with panel discussion and audience participation through a continuous theme of Re-aligning the Public's Trust in Pharmaceutical Medicines, Pharmaceutical Companies, Physicians, Principal Investigators, the Drug Discovery and Development Process, the Regulatory Agency, and the whole Scientific Community caring for Patients Wellbeing.

 The public is hearing a plethora of negative publicity about the entire medical industry, in general these days, including: concerns of drug safety and efficacy; Sponsors' Pharmaceutical Companies manipulating data for profit at the expense of the publics welfare; the morality and safety of the entire drug discovery and development process along with our regulatory agency, the FDA; whether it's time to have a new branch of the FDA in charge of reviewing and removing dangerous drugs that were inappropriately allowed on the market in the first place; along with the ethics and morals of the whole scientific community caring for patients' wellbeing. They are bombarded with advertisements from lawyers stating that your doctor gave you the wrong medicine that he knew was bad for you for the wrong medical reason and resulted in the injury you currently suffer with. The alternative medicines advertise themselves as curing everything without any side effects, reminiscence of the snake oil salesmen of the patent medicine years. The paradox is people are living longer, healthier, more productive and receiving better health care now than ever before. But, the perception is that the healthcare of yesteryear was better and that the entire industry is currently focused on the dollar and that we are blinded by greed and misdirecting our efforts to help people. The truth is the scientific method of medicine has advanced so far and the whole industry is providing such a greatly improved product with peer review scrutiny and introspection unparalleled that it's difficult for the doctor to understand why we are not revered as "rock stars" in stead of the "evil empire." People are frightened to accept our care that comes with a long list of disclaimers as "baggage." The current events issues people are hearing on a daily basis and are dealing with that shape attitudes concerning modern medicine include:

1. Press Reports of FDA Advisory Board Meetings.
2. Accusations of Corruption at the NIH from illegally breeding Chimpanzees in their labs to reports claiming the Bush administration ignored the principals of objectivity and impartiality and sought to manipulate the scientific process whenever it came into conflict with the White House political goals.
3. Fraud Convictions of Clinical Investigators like Dr. Robert Fiddes in 1997.
4. Conflicts of Interest between Researchers and Business Interests like came up in 2004 accusations that dozens of intramural scientist at the NIH allegedly receiving kick backs from sponsors.
5. Deaths of Subjects Enrolled in Clinical Trials like: Ellen Roche in 2001; Jesse Gelsinger in 1999; and a young healthy research assistant at the University of Rochester who volunteered as a subject in her own phase 1 trial in 1996.
6. Claims by Patients that they were not even informed that they were enrolled as a Subject in a Clinical Trial like the West LA VA in 1999.
7. Drugs being Withdrawn from the Market due to Safety Concerns now making Newspaper Headlines on a regular basis, including: Rezulin; Lotronex; Propulsid; Redux; Pondimin; Duract; Seldane; Hismanal; Posicor; Raxar, Vioxx, and Bextra.
8. The History of studies being performed on Vulnerable Populations, ie: prisoners, poor, etc.
9. The history of studies using Deception without proper consent and debriefing, ie: Stanley Milgram Obedience Trial and The Tea Room Study in the 1960s.
10. Duke Clinical Research Institute had to halt its research due to problems with its IRB in 1999.

 The first issue deals with the current climate of public opinion of "us" in clinical development being so low the time is right to reexamine the assurances by industry stakeholders and the safeguards for the public for their participation in pharmaceutical development. I will present the issues and we will discuss the current climate in clinical development from the PI's perspective.
 We have been receiving what seem to be continuous press reports of the FDA Advisory Board Meetings on the progress of the Cox-2 inhibitors. Almost one-third of the members on the FDA advisory committee that recommended in for the continued sale of COX-2 inhibitors "have consulted in recent years for the drugs' makers" and in large part voted in favor of the recommendation, according to a recent review of medical journals and other public records conducted by the Center for Science in the Public Interest, The New York Times reported (Harris/Berenson, New York Times, 2/25). The committee, which included members of the FDA arthritis and drug safety and risk management advisory committees, on Feb. 16th 2005, began three days of meetings to examine the safety of COX-2 inhibitors and make recommendations to the agency. Potentially this biased the decision to leave Bextra on the market in February 2005 and to consider returning Vioxx. Researchers with past financial ties to pharmaceutical companies often serve on FDA advisory committees, the Times reported. Although FDA has sought to "balance expertise with potential conflicts of interest," the inclusion of such researchers on agency advisory committees "has long been a contentious issue," according to the Times. Prior to each of the FDA advisory committee meetings on COX-2 inhibitors in February 2005, an agency secretary read a statement to absolve the potential conflicts of interest among committee members because the meetings involved "issues of broad applicability and there are no products being approved." The FDA secretary also said that the agency "acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussions before the committee, these potential conflicts are mitigated." Sheldon Krimsky, a science policy expert at Tufts University, said, "FDA has to work harder to fill panels with people without conflicts, and if they feel they have the best committee, they at least ought to make it transparent," Krimsky said. Daniel Troy, an attorney and former FDA general counsel, said the assumption that agency advisory committee members are influenced by past financial ties to pharmaceutical companies "buys into an overly conspiratorial view of the world" (New York Times, 2/25).
 The second issue deals with Accusations of Corruption at the NIH. In July 2001 the Coulston Foundation, a New Mexico primate testing lab, was hit with an unprecedented fourth set of federal charges for multiple violations of the Animal Welfare Act, In Defense of Animals and Animal Protection of New Mexico. The charges, filed by the U.S. Department of Agriculture on July 12, 2001 relate to the negligent deaths of two chimpanzees named Donna and Ray, inadequate veterinary care, inadequate veterinary staffing, conduct of unapproved research, and multiple violations of a federal consent order. They follow similar complaints filed by the USDA in July 1995, March 1998, and February 1999. Another issue is in reference to the Bush administration allegedly ignoring the principles of objectivity and impartiality and sought to manipulate the scientific process whenever it came into conflict with the White House political goals, as reported by Dee Ann Davis, Senior Science and Technology Editor, United Press International. She reported that the Public Faith in the science advice provided by the federal government took several hard hits during 2004, as politics and circumstance converged to undermine further the general credibility of science policy and federal researchers. Concerns voiced during the first few years of the current Bush administration grew louder as questions about appointees to science advisory boards, censorship of controversial research results by the government, and other matters undermining the trustworthiness of science policy decisions were collected and publicized by the Union of Concerned Scientists. There were two reports including a statement signed by 5000 scientists claiming the Bush administration ignored the principles of objectivity and impartiality and sought to manipulate the scientific process whenever it came into conflict with White House political goals. John Marburger, the president's science adviser, gave a long response that presented the bush administration's perspective on most of the issues raised by the UCS, but it did not appear to have persuaded the science community. The FDA's credibility took a blow during joint hearings into the poor handling of reports SSRI's increased suicidal behavior in children. Not long after the hearings, the FDA finally added warnings about the problems to the labels of the drugs. The public's reaction was that this appeared necessary and was seriously overdue. The FDA's credibility suffered yet another hit when Merck withdrew Vioxx in September 2004 after information came to light showing it increased the risk of heart attack and stroke. Soon after, doubts were raised about the safety of Aleve, Celebrex and Bextra. In April 2005 the Agency told Pfizer to remove Bextra against their will. The public is seeing in each case that the drugs had been approved by the FDA and stamped pure, safe and effective. The public raised concerns about the lax approach to adverse reports that arrive after a drug is on the market thru Med Watch. As more families are impacted by problematic prescription drugs, the calls for change in after-market testing and tracking; and at the whole FDA itself, are getting louder. Some call for a new agency to function alongside the FDA to be in charge of mandatory phase 4 studying drugs on the market and for assuring that the current knowledge supports their continued use, and to remove them the moment they are found unsafe. This will take a paradigm shift in everyone's thinking. First is, can the agency that approves drugs, the FDA, responsibly act to remove the drug that they said was good without looking like they made a mistake? Then, if we have a new agency in charge of these phase 4 studies, we are going to need the publics support to join these studies in unprecedented numbers. And, should we reserve NDA status until the drug is used in these new extended study periods or grand a limited availability to only the group of doctors willing to participate in these extended studies? In any event, the need to have the latest and the greatest cutting edge drug available now versus the need to be absolutely sure the drug doesn't have a one in a million side effect to ensure its safety are at odds with one another.
 The third issue is ensuring proper PI behavior in drug studies. Patients taking experimental drugs in clinical trials sometimes don't know the doctors administering them are usually paid by drug companies — and that the drugs can sometimes worsen their health. Increasingly, the ones doing these studies are no longer PhD researcher's at large universities. They're family doctors looking for extra cash - doctors like Robert Fiddes, who had a small practice in southern California. Susan Lester was one of his study coordinators. She says that he had 30 to 40 trials going during her time there. She says that drug companies were paying him anywhere from $50,000 to $250,000 per study. This can be a significant motivator for PI misconduct.
 The fourth issue occurred in 2004, as media reports and US congressional investigations revealed that dozens of intramural scientists and officials at the National Institutes of Heath had received substantial amounts of cash and stock options by consulting with drug and biotech companies, many of which had dealings with the Agency.
 The fifth issue deals with Deaths of Subjects Enrolled in Clinical Trials. Ellen Roche, a 24 year-old healthy volunteer in a phase one trial died in an asthma research trial at Johns Hopkins Medical Center in 2001 where she inhaled hexamethonium. The New York Times reported she died because of failure of scientists and administrators to recognize that the experiment was unsafe. In the fall of 1999, 18-year-old Jesse Gelsinger died as a result of his participation in a gene therapy trial. Jesse had a rare metabolic disorder, ornithine transcarbamylase deficiency syndrome (OTC), which was being controlled with diet and medication. Researchers were testing an innovative technique using adenovirus gene therapy. Shortly after treatment Jesse experienced multiple organ failure and subsequently died. This case catapulted research with human subjects into the national media. Serious concerns related to conflict of interest, data safety monitoring, and informed consent have made the Gelsinger case the most contemporary illustration of continued doubts about the ethical integrity of research with human subjects. This case has instigated deliberations on all these controversial topics at the national level. Jessie's father decided to sue after he found out the PI was not doing the research for the altruistic pursuit of knowledge but was part owner in the drug company and was going to benefit financially from Jessie's participation in the study. Death of a research assistant who volunteered for a study on March 31, 1996, a 19-year-old female Asian-American student at the University of Rochester responded to an advertisement for study patients to undergo bronchoscopy for the harvest of alveolar macrophages. The patient died of an overdose of lidocaine. The protocol didn't limit the dose. The pulmonologist didn't record the amount of lidocaine administered.
 The sixth issue occurred in April 1999 when all research projects at the Veterans Administration West Los Angeles Medical Center were shut down after many allegations of medical research performed on patients who did not consent. An investigation showed that not only was research being done on patients without who had not given informed consent, but also that research was being done on patients who had expressly refused consent.
 The seventh issue involves drugs being withdrawn from the market due to safety concerns now making Newspaper Headlines on a regular basis, including: Rezulin; Lotronex; Propulsid; Redux; and, Pondimin. This was made worse by a FDA official, Dr. David Graham listing five other drugs that he feels are bad and should be pulled off the market, but his colleagues at the FDA disagree with him. He accuses his colleagues of having alteria motives. The five drugs include: Serevent, Crestor, Accutane, Meridia, and Bextra. Well, the Bextra is gone now. And, lawyers are advertising like mad with lists of drugs that are pages long stating that if you took this drug, we will help you sue your doctor.
 The eighth issue is about the history drug studies being done on vulnerable populations. These range from using prisoners for studies as in ancient Egypt, the first century physician Celsius justified experiments on condemned criminals using words which became the classic defense for hazardous experimentation: "It is not cruel to inflict on a few criminals sufferings which may benefit multitudes of innocent people through all centuries." The Wichita Jury Case, which occurred in 1953, University of Chicago researchers? tape-recorded the deliberation of juries in six civil cases, with the consent of the judge and counsel for both sides, but without the jurors' knowledge. The researchers were investigating whether the comments of some lawyers might have inappropriately affected the deliberative process. When word of the research leaked out (one of the tapes was played at a Bar Association conference), public outrage led to Senate hearings chaired by James O. Eastland. Even though there was no evidence that the recording had influenced the actions of the jury, it was felt that the possibility of further recordings being made might affect jurors' statements or deliberations. A federal law was passed in 1956 banning all recording of jury proceedings. Timothy Leary and Richard Alpert case which occurred in the 1960s where these two Harvard faculty (Leary was lecturer in Social Relations and Alpert was assistant professor at the Ed School) worked together at the Center for Research in Personality. Hallucinogenic drugs were not then illegal and they experimented with psilocybin and LSD obtained from Sandoz Pharmaceuticals, which were also dispensed to friends, associates and students. As time passed, the research became more and more freewheeling and, in the opinion of many departmental colleagues, rapidly lost any semblance of academic rigor. At this time the University Health Services was just formulating its policies regarding the use of human research subject volunteers. An agreement was reached with Alpert and Leary in the fall of 1961 that they would not include any undergraduates in their research. In early 1962, the two separated their activities from the Center for Research in Personality and formed their own private organization, the International Federation for Internal Freedom (IFIF). Eventually, both were fired from the university, Alpert for having given psilocybin to an undergraduate in 1962 in violation of the UHS agreement, and Leary for failing to teach his scheduled classes in the spring of 1963. The Jewish Chronic Disease Hospital Study in 1963 where studies were undertaken in Brooklyn, NY, at the Jewish Chronic Disease Hospital, which is now called Interfaith Hospital of Brooklyn. The doctors then did a terrible "study" on unwitting, unsuspecting, unconsenting patients on the body's ability to reject cancer cells. They injected live cancer cells intravenously into patients and watched to see if they developed any signs of neoplasia. They then proudly published their results for the world to read. The Willowbrook Study which occurred in the early 1960s where unethical research was conducted at the Willowbrook State School in Staten Island, NY, on vulnerable mentally retarded children to better understand the natural history of the hepatitis virus. Most of the kids "caught" the highly infectious virus after they came there. The doctors then decided to "coerce" the parents into enrolling their children in an experimental study whereby their children were deliberately infected with the live hepatitis virus. Only parents who agreed to the research were able to get their retarded children into Willowbrook! This controversial case raised important questions about the adequacy and freedom of consent, inadequate disclosure of the child's risk of later developing chronic liver disease, and the lack of information given to parents about access of doses of gamma-globulin.
 The ninth issue involves the history of studies using deception without proper consent and debriefing. Tea Room Study occurred in the 1960s, there was a study on the homosexual practices in public restrooms, then, to contact the men at a later time to conduct further investigation on their behavior. The researcher went undercover and gained the confidence of the gay men. He identified 100 active participants by tracing their car license numbers. A year after he completed the initial study, he distributed a "social health survey" throughout the communities where he knew the participants lived. The ethical problems were: use of a vulnerable population, reinforced the image that social scientists use deception casually in research, and lack of proper informed consent. Humphreys, Laud. Tearoom Trade: Impersonal Sex in Public Places. Walter de Gruyter, Inc, February 1975. Human Radiation Experiments occurred between 1944 and 1974 where the government sponsored several thousand human radiation experiments and told people they were participating in something else. They involved exposing people to radioactive tracers in doses likely to cause physical harm. During this time there was little attention paid to issues of fairness in the selection of the participants. Research was conducted without their awareness or consent and on participants not likely to derive any directly medical benefit. These research errors were finally exposed in 1993! And in 1994, President Clinton created the Advisory Committee on Human Radiation Experiments to identify ethical and scientific standards for evaluating these events, and to make recommendations to ensure that past wrongdoings cannot be repeated. The Tuskegee Syphilis Study began in 1932 enrolling poor black men with syphilis in a drug trial where they didn't receive any drug and were told lies about the efficacy of the treatment. This was further exacerbated by deliberately withholding and preventing them from receiving penicillin when it was invented in 1942. The study was ended in 1972 when a reporter exposed the story. President Clinton issued a formal apology in 1997. Also, in the early 1960s, Stanley Milgram's research on obedience to authority harmed subjects by making them believe they were shocking to death their poor performing students to test the theory that Americans are different than Germans and would not blindly follow wrong orders. The subjects were not informed what type of study they were getting into nor were they adequately debriefed.
 The tenth issue involves Duke Clinical Research Institute had to halt its research due to problems with its IRB in 1999. A major teaching Hospital doing things wrong makes the public think our system is broken and in desperate need of repair.
 So, when you ask a subject to sign an ICF, these events can cause your patient concern. What the PI should point to is the many positive things that where done to ensure subject safety and welfare including:
 In 1953, the first IRB came out of an NIH Policy on the protection of human research subject volunteers.
 The Declaration of Helsinki: first adopted in 1964 and subsequently updated, makes additional safety recommendations to the Nuremberg Code including preliminary experiments on animals, IRB procedures and DSMBs.
 The Public Health Service was created in 1966 providing volunteers with IC via an ICF. This led to expanded role of the IRB as an oversight arm of the research process.
 In 1979, the Belmont Report was released by the National Commission for the Protection of Human Subjects of Biomedical and Behavior Research, entitled: Ethical Principles and Guidelines for Research Involving Human Subjects. It identified the three principles: Respect for Persons; Beneficence; and Justice.
 In 1980, the FDA established the Code of Federal Regulations (CFR) to establish regulations on the protection of human subjects.
 In 1982, CIOMS (Council for the International Organization of? Medical Sciences) published the International Ethics Guidelines for Biomedical Research Involving Human Subjects. This is to help guide drug study ethics in third world areas.  In 1989, the PHS (Public Health Service) created the OSI (Office of Scientific Integrity) and the OSIR (Office of Scientific Integrity Review) which were consolidated in May 1992 to the ORI (Office of Research Integrity) to deal with scientific misconduct.
 In 1991, The Common Rule 45CFR46 became a federal policy for the protection of human subjects revised in 2001.
 In June 1996, ICH-GCP Harmonized tripartite Guideline to provide standards for research among EU, Japan, USA.
 In 1997, the Food and Drug Administration Modernization Act further improved regulation of drugs.

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
PI (Principal Investigator), DSI (Drug Study Institute)
Board Certified Internist, JPMC (Jupiter Preventive Medicine Center)
DABIM (Diplomat American Board of Internal Medicine)
FACP (Fellow American College of Physicians)
CPI (Certified Physician Investigator) by the AAPP (American Academy of Pharmaceutical Physicians)
CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals)
CCI (Certified Clinical Investigator) by the DIA (Drug Information Association)
CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals)
CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates)
Founder, CertifiedResearchers.com
IRB Member, Jupiter Medical Center
Expert Medical Witness, ExpertMD