Yesterday, today, and tomorrow Research Pharmacy Yesterday, today, and tomorrow

Goals of this presentation : A look at clinical research from a pharmacy point of view. What will NOT be a focus of this presentation: Social and ethical questions and considerations Legal and regulatory issues Protocol development and IND applications Statistical considerations in clinical trials Good morning. My goal today is to present a brief overview of clinical research from a pharmacy point of view. Many of you may be involved in varying degrees with supporting clinical trials and much of what I will present today will already be very familiar to you. Others may have less familiarity with clinical trials and hopefully some of my comments today will be informative and possibly helpful. But before I get into the body of my presentation I feel that I need to make a bit of a disclaimer. Clinical research is a multifaceted activity involving a number of different groups and individuals that must work together in order for any clinical trial to be conducted in a safe and productive manner. There are a number of issues related to the conduct of human research in general that are very important and essential to the development of ethical and responsible clinical trials. Unfortunately there is not time in one presentation to fully address all of these issues. As a result, there are some topics which, while they are important and many will be mentioned and some discussed briefly, they will not be a focus of my talk this morning. These include:

Why do we do research? Improve patient health through improved patient care Types of studies: Observational: e.g. epidemiologic, cohort, case control, longitudinal, etc Interventional

Interventional clinical trials Clinical trials allow us to evaluate the efficacy and safety of new medications or agents Usually in comparison to an established standard of care Randomized, double-blind studies (the “Gold Standard”)

Why do we do interventional clinical trials? To obtain data to present to the FDA ! Drug companies are trading drug (and medical care) for data on patient outcomes Most interventional clinical trials are conducted to generate data which can then be presented to the FDA in order to obtain approval for a new drug or a new use of an approved drug. Sponsors, that is drug companies, are trading the drug (at no cost to the participant) and medical care in exchange for the data generated by the study. Another reason we do interventional clinical trials is to pay the bills (more on that later).

Stages in drug development Drug discovery / development Pre-clinical testing Investigational New Drug application (IND) Clinical testing Phase I Phase II Phase III Phase IV

Phase I trials First use of a new drug in humans Small numbers of patients, usually healthy volunteers Looking primarily at safety and dose determination Safety – dose limiting toxicity (DLT) Dose determination – increase dose to toxicity Pharmacokinetic and pharmacodynamic studies

Phase II trials Determine short-term risks and safety Looking at effectiveness and best tolerated dose level Dose(s) based on information from Phase I studies Also looking at side effects Study subjects are the types of patients the agent is intended to treat

Phase III Large scale trials (e.g. 300 – 1000+ subjects) looking at safety and efficacy usually in a randomized, controlled fashion often involving multiple centers Seek to assess risk/benefit ratio and gather date for FDA approval of the agent / labeling If data gathered from Phase I, Phase II, and Phase III trials demonstrate safety and efficacy => New Drug Application (NDA) may be filed with the FDA

Phase IV trials Post approval studies May be required as a condition of approval Long term safety studies Comparison studies

Important elements in clinical trials The protocol The informed consent Regulatory bodies Blinding Randomization Finance

The Study Protocol Common elements: Title Protocol summary or synopsis Background and rationale Study design / investigational plan Randomization and blinding The investigational product Inclusion and exclusion criteria Adverse events Data analysis

Informed Consent Form (the ICF) Background Elements Description of trial Voluntariness / withdrawal of consent / alternatives Risk / benefit ratio Questions Contacts Signatures The process of obtaining informed consent is an essential part of the ethical conduct of clinical research . The basis for informed consent lies in the principles of autonomy and respect for persons. The Belmont Report produced by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1978 established three principles for ethical human subjects research; respect for persons; beneficence (having the good of the subject as a goal of the research); and justice. The need for such protection of subjects was a result of research abuses that have occurred over time. Examples of such abuses include much of the medical research carried out by the Nazis during World War II; the syphilis study conducted in Tuskegee, Alabama from 1932 until 1972 and which was sponsored by the U.S. Public Health Service; and studies conducted by the U.S. Public Health Service from 1946 to 1948 that involved exposure and infection of subjects from vulnerable populations to sexually transmitted diseases without obtaining informed consent.

Regulatory bodies Institutional review board (IRB) – patient protection Institutional bio-safety committee (IBC) and the Recombinant DNA Advisory Committee (RAC) Food and drug administration (FDA) Compliance office / office of research integrity (ORI)

Blinding Single vs double blind Physical blinding: Size, shape, taste, appearance, smell, etc. Time considerations Double dummy designs Blinding is a major concern in most clinical trials, as the breaking of the blind for a patient or a nurse or physician involved in the care and treatment of study patients, potentially invalidates the data from that patient and is a disservice to the study and the patient. Sponsors need accurate, “clean” data to present to the FDA and inadvertently un-blinded patients do not fit this description. Single vs double blind studies Matched placebo – only available from company Time considerations: the time for a dose of IV study medication to be available, should be at the same for active drug and placebo (even if the preparation of the active drug takes longer)

Randomization History IVR and IWR systems Stratification Blocks

Finance Contracts and grants (OCGM) Cost of doing a study Conflict of interest concerns

The “Players” Patients The PI (and sub I’s), the 1572 form (Statement of Investigator) Monitors Research Coordinators Regulatory entities (IRB, IBC, FDA, ORI / compliance, etc) CRO’s

The “Players” (continued) Support services Laboratory Radiology Pharmacy Statistics Finance “Active“ support services: lab, radiology, nuclear medicine, pharmacy, etc. These are entities that provide support for the treatment, evaluation, and monitoring of subjects during the course of the study. The cost of these services should be known and taken into account when the study contract is being determined. Likewise, services like biostatistics, which may be involved in the collection and analysis of data at the end of the study, need to be identified and taken into account when determining the study budget.

In the beginning… “What’s this and where did it come from?” (x2) “…and you’re also in charge of investigational drugs.” “I think it’s in that cabinet over there next to the sink” “We are missing a week’s worth of entries on the temp record.” “Is this the next envelope?” “I’m going to San Diego for a meeting!” “Budgets???”

The present Personnel Types of studies Training Records and documentation Monitoring Disposal of study materials As clinical research has become more widespread, more and more pharmacists are being exposed to interventional clinical trials and the pool of pharmacists with some degree of research experience is growing. While handling the investigational drugs may still be only one of many duties for these pharmacists, their ability to meet the requirements of the studies has increased. Many of the studies now being supported by research pharmacies are more involved, more complex or involve more hazardous materials and require more careful handling. The maintenance of proper storage conditions and adequate security for investigational agents is a major concern for sponsors. New drugs are expensive and the need to be able to document the proper storage of investigational drugs has lead to the use of temperature tracking devices being included in shipments of refrigerated or frozen IP’s and temperature monitoring of ambient, refrigerated, and frozen storage conditions. Dispensing: track everything – track nothing Remote monitoring Disposal on site

Elements of a Research Pharmacy Personnel Storage space / equipment Temperature monitoring Documentation / record retention The “information sheet” or “summary sheet” Study budget As I mentioned earlier that the number of pharmacists with some degree of familiarity with clinical trials is increasing as clinical research becomes more prevalent. This helps in identifying primary research pharmacist or the “pharmacist of record”. What we have to realize, however, is that having only one pharmacist in charge of investigational drugs is not sufficient. Most errors, from preparation and labeling errors to documentation errors occur when the “IDS Pharmacist” is not present and someone else is trying to cover. Fro this reason it is important to identify a back-up research pharmacist or pharmacists. One other consideration is to have a technician that works with the research pharmacist and is familiar with the active studies and the drugs involved. A good, well trained technician can perform many of the activities required by a protocol including acknowledging receipt of drug, randomizing patients, preparing study medication, and record keeping. Having a research technician can provide much of the continuity and support need when the primary research pharmacist is not available. Space / storage - secure area, limited access, locked cabinets or refrigerators and freezers, separate from regular medications Equipment – failures mean quarantining all drug, notifying sponsors or monitor, documenting what happened , and finding out if drug can still be used or must be replaced.

Pharmacy study budgets Common Elements Start-up Maintenance Randomization Study drug preparation and dispensing Close-out fee On – call fees Start up

What’s ahead? Why utilize pharmacy services? Exotic agents Electronic data capture and records Impact of healthcare systems Community based research Why – Pharmacy support will be necessary for comlex protocols involving hazardous agents or agents which require complex preps (e.g. sterile products in a sterile syringe / IV bag). Pharmacists will need to maintain high levels of proficiency in preparing sterile products. Agents – gene therapy agents, vaccines, new oncologic agents, etc Electronic data entry will continue to expand - electronic signatures; electronic drug Accountability Logs?? Healthcare systems – systems now much more prevgelant and continuing to expand. One potential benefit of a system is the ability to share information and processes – share protocols among member institutions. Use of one “IRB of record” and similar budget / contract agreements. PLUS - systems can provide resources (information sheet; budgets; policies and procedures, etc. Community – more studies in non acute care settings; e.g. practice groups, community health centers, etc