Clinical Trials

Parkinson Study Group is your partner in clinical trials from start to finish. As North America’s largest pro-active, not-for-profit scientific network of Parkinson Centers, we will provide optimal resources to assist you in planning, executing and dissemination of results. Learn more about our comprehensive services, superb track record and uncompromised reputation below.

TESTING OF EXPERIMENTAL DRUGS IN HUMANS

Before a medication can be sold over the counter or with a prescription, it must undergo rigorous testing. The process by which new medications are tested so they may ultimately be marketed to treat or cure various diseases or conditions is as follows:

  1. Development of a Compound
    Chemists in a laboratory develop compounds with a certain chemical structure that the scientists believe may function in humans to alleviate certain symptoms in a disease, or perhaps even cure it.

  2. Pre-clinical Testing
    To prove that the compound works as is hypothesized and does not produce any negative side effects, it is first thoroughly tested in animals (e.g.., mice, rats, dogs, monkeys). This stage of testing is commonly referred to as the “pre-clinical” stage. The purpose of these animal studies is to prove that the drug is not carcinogenic (cancer causing), mutagenic (causing changes in the genetic material), or teratogenic (causing fetal malformations), and to understand how the drug is absorbed and excreted. Once a pharmaceutical company proves that the compound appears to be safe, and possibly effective in animals, the company will provide this information to the Food and Drug Administration (FDA) requesting approval to begin testing the compound (experimental drug) in humans via an Investigational New Drug (IND) application.

  3. Clinical Trials/Studies in Humans
    The clinical testing (investigation) of experimental drugs (previously unproven in humans, therefore “experimental”) in humans is normally done in three phases (Phase I, II and III) with more and more people included in each subsequent phase. Although in general the phases are conducted sequentially, they may overlap. The three phases for testing experimental drugs are as follows:

    • Phase I Clinical Studies
      Phase I studies are primarily concerned with the drug’s safety, and are the first time the drug is tested in humans. These studies are typically done in a small number of healthy volunteers (20- 100), usually in a hospital setting where the volunteers can be closely watched and treated should there be any side effects. These volunteers are usually paid for their participation and for the most part tend to be men (approximately 30 years of age on average). The purpose of these studies is to determine how the experimental drug works in humans. That is, how is the drug absorbed, metabolized, and excreted. Additionally, they seek to determine what types of side effects occur as the dosage levels (that is, the amount of drug) are increased, as well as to obtain early evidence on drug effectiveness.

      The PSG has not been involved in Phase I testing. However, it is during Phase I testing that the PSG is collaborating with the pharmaceutical company to plan Phase II and III clinical trials in Parkinson’s disease.

    • Phase II Clinical Studies
      Once an experimental drug has been proven to be safe and well tolerated in healthy volunteers, it must be tested in the patients that have the disease or condition that the experimental drug is expected to improve/cure. In addition to ensuring that the experimental drug is safe and effective in the patient population of interest, Phase II studies are also designed to evaluate the effectiveness of the drug. The second phase of testing may last from several months to a few years and up to several hundred patients. Most Phase II studies are well controlled, randomized trials. That is, one group of patients (subjects) will receive the experimental drug, while a second “control” group will receive a standard treatment or placebo. Placement of the subject into the drug treatment or placebo group is by random chance (as if by the flip of a coin). Often these studies are “double-blinded”, that is, the patient nor the researchers (investigator, coordinator, etc.) know who is getting the experimental drug. Additionally, Phase II studies are often designed to determine the correct dosage, that is the dosage with the least number of side effects that is most effective. These are often referred to as dose-ranging studies. In general, the purpose of Phase II studies is to provide the pharmaceutical company and the FDA comparative information about the relative safety of the experimental drug, the proper dosage, and the drug’s effectiveness. Only about one-third of experimental drugs successfully complete both Phase I and Phase II studies.

      The PSG has been heavily involved in the Phase II testing of numerous experimental drugs for PD. Many of these experimental drugs moved into Phase III testing and were ultimately approved by the FDA for use in PD.

    • Phase III Clinical Studies
      In a Phase III study, an experimental drug is tested in several hundred to several thousand patients with the disease/condition of interest. Most Phase III studies continue to be randomized and blinded. The large-scale testing provides the pharmaceutical company as well as the FDA with a more thorough understanding of the drug’s effectiveness, benefits/risks, and range/severity of possible adverse side effects.

      Phase III studies typically last several years. Seventy to 90 percent of drugs that enter Phase III studies successfully complete this phase of testing.

  4. Marketing of New Drugs
    After successful completion of Phase I-III testing, a company will submit the results of all of the studies to the FDA to obtain a New Drug Application (NDA). Once the FDA grants a company with a NDA, the company can market the drug (medication) to the public. Additional testing (post-marketing or late phase III/phase IV) to look at the long-term safety continues.

  5. What about Natural Remedies?
    Patients are often interested in natural treatments of Parkinson’s disease. It is important to understand that “natural” products are not subjected to the kind of rigorous testing outlined above. Therefore data are not always available for the safety or effectiveness of these treatments.

The Study Budget Committee, as described in the PSG Policies & Procedures, is responsible for developing site and “per subject fee” costs for study budget proposal purposes. The Committee will be responsible for providing uniform site and “per-subject-fee” budgetary input for all PSG projects. Costs shall be representative of the needs of the majority of PSG sites. The Committee will also be the focal point for considering changing and newly emergent issues related to site compensatory issues and shall make recommendations on site budgetary issues to the PSG Executive Committee.

Background:

For all PSG studies, a budget must be formulated that includes elements to cover site costs for the evaluation of study participants (the “per-subject fee”, PSF). A long-standing principle of the PSG is to develop a uniform rate for site payment and the PSF. It is desirable for the PSF to reflect a rate that will allow for fair compensation to sites such that the decision of a site to participate is not unduly influenced by compensation issues. Indirect rates vary by institution and PI’s need to take this into consideration. All PIs are required to obtain Study Budget Committee review prior to submitting their budget to the proposed sponsor.

Composition of the Study Budget Committee:

  • The PSG Executive Committee will appoint 3 investigator and 3 coordinator PSG members for 3 year terms.
  • One of the members is appointed the Committee Chair, who is responsible for organizing and representing the consensus of the group. The Committee may seek advice from people not on the committee from time-to-time.

Sample Process:

  1. The PSG Administrative Manager provides the study PI with historical PSF’s, broken down by activity (eg vital signs), indicating more recent PSFs.
  2. The PI chooses an appropriate cost per activity based on past PSFs and his/her expertise and judgment. A total PSF is constructed from the individual items.
  3. The PSG Administrative Manager emails the protocol synopsis, schedule of activities and Excel budget page to the Committee requesting comments on the budget proposal.
  4. The Committee chair asks Committee members to forward their review of the proposed PSF and condenses their comments.
  5. The Committee chair communicates the comments to the PI, who has final authority to set the PSF.

Benefits:

  • Efficiency in the development of the PSF
  • Explicit process known to the PSG membership Committee participation promotes learning and improves consistency in PSF preparation
  • Provides Study PI with a consensus-driven PSF justification during negotiation with sponsors.

Clinical Trial Updates

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SPARK

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Pharmacokinetics, and Pharmacodynamics of BIIB054 in Subjects with Parkinson’s Disease

This study is now closed for participation recruitment.

The Parkinson Study Group (PSG) is conducting the North American arm of this global study, under the direction of Andrew Siderowf, MD, a Phase 2a, randomized, double-blind, placebo-controlled trial to to evaluate the dose-related safety of BIIB054, to evaluate the pharmacodynamic effects of BIIB054 on the integrity of nigrostriatal dopaminergic nerve terminals, to assess the pharmacokinetic (PK) profile of BIIB054 and to evaluate the immunogenicity of BIIB054 in subjects with Parkinson’s disease.

The trial is funded by Biogen and registered on clinicaltrials.gov (NCT03318523).

SPARX3

Study in PD of Exercise (Corcos,PI)

Enrollment is now open.

A new Phase 3 multi-site clinical research trial from Northwestern Medicine will test if high-intensity treadmill exercise is more effective in decreasing the signs of Parkinson’s disease in individuals who have not initiated medication for Parkinson’s. 29 sites (27 in U.S. and 2 in Canada); has added Morehouse, PSG’s first HBCU- based site. Funded by NINDS.

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PD GENERATION

Mapping the Future of Parkinson’s Disease

People with Parkinson’s can receive genetic testing and genetic counseling by participating in PD GENEration, sponsored by the Parkinson’s Foundation in partnership with the Parkinson Study Group.

PD GENEration: Mapping the Future of Parkinson’s Disease, is a first-of-its-kind national initiative that offers free genetic testing for clinically relevant Parkinson’s-related genes and free genetic counseling to help participants better understand their results. Additionally, genetic testing results obtained through this study will be de-identified and stored in a secure central database for future Parkinson’s-related research.

As a result of COVID-19, the Parkinson’s Foundation expanded their study to offer virtual participation nationwide through telemedicine with an at-home cheek swab kit. The study has enrolled over 400 participants to-date.

Click here to learn more about PD GENEration or if you are interested in enrolling in this study.

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TOPAZ

Trial of Parkinson’s And Zoledronic Acid (Tanner, Co-PI)

Enrollment is now open.

A remote home-based clinical trial to determine whether or not a single dose of zoledronic acid can prevent fractures and reduce mortality in people over 60 with PD and other types of neurodegenerative parkinsonism. The trial is sponsored by the NIH and is a partnership with the Parkinson’s Foundation. Currently expanding PSG site participation . A paper describing the TOPAZ study design is newly published.

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EARSTIM

The Stoparkinson Earstim-PD study is moving along! The virtual Investigator-Study Coordinator meeting held on February 20, 2021 was well attended. Site Initiation visits (SIVs) are currently being scheduled for this 8 site US, prospective, randomized, double-blinded sham-controlled, within-subject design, 3-treatment, 3-period crossover study that is expected to enroll 38 subjects with Parkinson’s Disease who have the wearing off phenomenon on oral levodopa therapy. All participants will receive 3 treatments on different days, each with different stimulation conditions. All subjects will wear the Earstim device on the ear ipsilateral to the side of the body more affected by Parkinson’s for 120 minutes during each of the 3 treatment applications.

Observational Trials

Click to enlarge graph.

AT-HOME PD

Tele-health outcomes as digital biomarkers of Parkinson’s disease progression during extended follow-up of STEADY-PD III and SURE-PD3 trial participants.

AT-HOME PD enrolled 226 participants –125 and 101 from the STEADY-PD IIIand SURE-PD3 clinical trials, respectively, to follow them for two more years by a) annual tele-visits with a movement disorders neurologist, b) quarterly smartphone tasks(via the mPower app) and c) patient-reported outcomes(via Fox Insight). As of May 10, 2021, 137 members of this original cohort have completed the final study tele-visit (V02; graph below).

In late 2019, to help validate the tele-visit against the in-person visit the study protocol was amended to include a sub-study in which participants from the SUPER-PD study at University of Rochester would participate in a single tele-visit within two weeks of their most recent in-person SUPER-PD study visit. As of May 10, 2021, 34 participants have enrolled in and completed the SUPER-PD sub-study of AT-HOME.

Due to the increased demand for research tele-visits created by the COVID-19 pandemic, the AT-HOME PD study shared its experience including the study protocol via the study’s website (https://www.athomepd.org/professionals) with other ongoing clinical studies and research professionals seeking to convert to remote assessments. In December 2020 the AT-HOME PD team published a paper in Annals of Clinical and Translational Neurology with the objective of outlining the study methodology and providing guidance on how to launch and conduct virtual PD studies.

The trial is registered on clinicaltrials.gov (NCT03538262).

FIRE-UP PD

Fostering Inclusivity in Research Engagement for Underrepresented Populations in Parkinson’s Disease

In recent years, scientists have learned that improving representation of all people in clinical research is an important way to fully understand diseases. This ensures that new treatments work well for everyone. However, appropriate representation in clinical research for Parkinson’s disease has been difficult. Some recent studies have reported that more than nine in 10 research participants are non-Hispanic Caucasian even though Parkinson’s disease affects people from all walks of life. While scientists understand some of the barriers preventing certain groups from participating in these studies, many solutions have not been tested. Led by Jonathan Jackson, PhD of the Community Access, Recruitment & Engagement (CARE) Research Center at Massachusetts General Hospital, the FIRE-UP PD study focuses on improving awareness and participation from groups and communities that are not often part of Parkinson’s research studies. The study tests new ideas to raise awareness of Parkinson’s research studies, particularly for the online study, Fox Insight.

This study will take place in movement and disorder clinics around the United States. Half of clinics will develop individual plans to raise awareness of the Fox Insight study to underrepresented patients and fellow neurologists. These will be compared to control clinics who simply display Fox Insight study materials in waiting rooms, which is often how clinical studies are advertised. After a six-month period, the clinics with individual plans will be compared to one another, as well as to the clinics who only displayed information in waiting rooms. Researchers will be looking not only at which clinics can enroll underrepresented groups to Fox Insight but also how aware, interested, and engaged patients and their neurologists are with regards to the Fox Insight study.

This study may help underrepresented groups access Parkinson’s research studies. The study results may also have an impact beyond Parkinson’s research. Scientists believe that barriers preventing certain groups from participating in Parkinson’s research are similar to barriers preventing those groups from timely Parkinson’s diagnosis and treatment. Improving representation in Parkinson’s research is a key step towards improving access to Parkinson’s diagnosis and treatment for everyone.

This study is funded by the Michael J. Fox Foundation and is distributed through Massachusetts General Hospital.

RAD-PD-LOGO

RAD-PD

Registry for the Advancement of Deep Brain Stimulation in Parkinson’s disease

RAD-PD is a quality improvement patient registry that systematically and prospectively characterizes a large cohort of patients with Parkinson’s disease (PD) undergoing deep brain stimulation (DBS). The project is funded by the Michael J Fox Foundation and the Neuropoint Alliance serves as the data management and coordinating center. By assessing real-world DBS care, RAD-PD seeks to identify best practices surrounding DBS for PD, investigate adverse effects and their determinants, and describe the disparities in outcome and health economics of DBS. The project launched in October 2018 with the first patient enrolled in March 2019. Although 2020 was a difficult year for RAD-PD due to nationwide pandemic shutdowns, registry leadership and management successfully relaunched the project in a new data management platform. As of April 2021, close to 130 patients are enrolled in the registry from 20 participating sites and ongoing data collection is occurring, with new patient recruitment, and surgical and 6-month follow-up data being actively collected. A presentation describing the registry was presented at the 2021 North American Neuromodulation Society meeting and a poster describing the baseline characteristics of a subset of the enrolled cohort was presented at the 2021 American Academy of Neurology Annual Meeting.

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WATCH-PD

A Multi-center, Prospective, Longitudinal, Digital Assessment Study of Disease Progression in Subjects with Early, Untreated Parkinson Disease

The PSG, under the direction of Ray Dorsey, MDMBA and Jamie Adams, MD (University of Rochester) is conducting a multi-center, observational study in individuals with early, untreated PD. The purpose of the WATCH-PD study is to obtain and compare information on early PD progression from traditional examinations and questionnaires with health-related information from wearable sensors and study-supplied mobile devices (smartphone and watch). Funding for the trial has been generously provided by Biogen and Takeda.

The trial is registered on clinical trials.gov (NCT03681015). This study completed enrollment on 12/28/2020. 82 PD participants and 50 control participants were enrolled at 17 PSG sites across the US. Currently, 23 participants have completed the trial, and all month 1 and month 3 visits have been completed.

A WATCH-PD participant webinar was presented on 2/24/2021 which demonstrated the baseline information participants and the data the study is planning on collecting. Future participant webinars are planned as the study progresses.

To learn more, or if you’re interested in participating in the study, visit the WATCH-PD website.

Completed Clinical Trials -
Analysis/Publication Phase

NIC-PD (A Randomized, Placebo-controlled, Double-blind, Multi-centre Trial to Assess the Disease-modifying Potential of Transdermal NICotine in Early Parkinson’s Disease) in Germany and the USA.
Status, January 29, 2018: Manuscript Phase

The Parkinson Study Group (PSG), under the direction of Wolfgang Oertel, MD (Philipps University, Marburg Germany), and James Boyd, MD (University of Vermont), conducted a randomized, placebo-controlled, double-blind, multi-center trial to assess the disease-modifying potential of transdermal nicotine in early Parkinson’s disease in Germany and the USA. The purpose of the study was to demonstrate that transdermal nicotine treatment retards disease progression as measured by change in the Unified Parkinson’s Disease Rating Scale (UPDRS) (part I, II, III) score between baseline and after 52 weeks of study treatment plus two more months following a wash-out period (60 weeks). Approximately 20 research centers in the United States and Germany enrolled approximately 160 subjects for 12 months each.

This study was conducted under two research grant awards from The Michael J. Fox Foundation one to Philipps University, Marburg, Germany and the other to the University of Rochester, Rochester, New York.

If you are interested in learning more about this study, please see the study on www.clinicaltrials.gov

NILO-PD
Status, October 22, 2019: Analysis Phase

The Parkinson Study Group (PSG), under the direction of Tanya Simuni, MD (Northwestern University) conducted a multi-center, randomized, double-blind, placebo-controlled study of nilotinib in individuals with moderate to advanced Parkinson’s disease (PD). Nilotinib, a U.S. Food and Drug Administration (FDA)-approved treatment for chronic myelogenous leukemia, is one of many examples of a repurposed (or repositioned) drug for Parkinson’s.

The trial is registered on clinicaltrials.gov (NCT03205488). Results of the study will be presented at the MDS-PAS Congress, February 2020, in Miami.

NoMOFA (Validation of a Non-Motor Fluctuation Assessment Instrument (NoMoFA) for Parkinson’s Disease)
The study completed enrollment in December 2019. Data analysis has demonstrated that the questionnaire is valid and reliable. Additional Delphi Panel was convened and resulted in finalization of the questionnaire. The results of the study were presented as part of the Guided Poster Presentations at the 2020 MDS Virtual Congress in September 2020. The manuscript has been submitted for publication in the Movement Disorders Journal and is under review.

The Parkinson Study Group (PSG), in collaboration with Galit Kleiner, MD (ATC), Alberto Espay, MD (University of Cincinnati), Hubert Fernandez, MD (Cleveland Clinic), Alfonso Fasano, MD, PhD (TWH), Kelvin Chou, MD, PhD (University of Michigan), and Glenn Stebbins, PhD (Rush University), have developed a comprehensive questionnaire that assesses the presence of non-motor fluctuations (NMFs) in individuals with Parkinson’s disease (PD). The objectives of this validation study are to: (i) assess the scale’s internal consistency and item-to-total correlations; (ii) assess test-retest reliability; (iii) use factor analysis and reliability measures to guide item reduction; (iv) assess construct validity; (v) assess the scale’s ability to discriminate between static non-motor symptoms and non-motor symptoms which fluctuate; and (vi) estimate the relative distribution of cognitive, psychiatric, autonomic, sleep and sensory NMFs in PD patients with motor fluctuations and their impact on quality of life in Parkison’s disease.

The study is sponsored by Sunovion Pharmaceuticals and is registered on clinicaltrials.gov.

STEADY-PD III
The Parkinson Study Group (PSG), under the direction of Tanya Simuni, MD (Northwestern University), and Robert G. Holloway, MD, MPH (University of Rochester), conducted a multi-center, randomized, double-blind, placebo-controlled study of isradipine in individuals with early Parkinson disease (PD) called STEADY-PD III: Efficacy of Isradipine in early Parkinson Disease. The purpose of STEADY-PD III was to assess the potential effect of isradipine on slowing the progression of PD. To view the results of this study, click here.

SURE-PD3 (A Phase 3, Randomized, Double-blind, Placebo-controlled Trial of Urate-elevating Inosine Treatment to Slow Clinical Decline in Early PD)
Closing out. Negative results of primary analysis presented at MJFF Therapeutics Conference 2019. Secondary analyses incorporating WGS data are in progress and will coordinate with STEADY-PD III analyses.
The Parkinson Study Group (PSG) conducted, under the direction of Michael Schwarzschild, MD PhD, a placebo-controlled, randomized, double-blind study to assess the disease-modifying potential of the drug inosine in people with early stage Parkinson’s disease (PD).

SYNAPSE
The Parkinson Study Group (PSG), under the direction of the SYNAPSE Steering Committee, conductedd a placebo-controlled, randomized, double-blind study called SYNAPSE: (SYN120 a Dual 5-HT6/5-HT2A Antagonist Proof of Concept Study to Evaluate Its Safety, Tolerability and Efficacy in Parkinson’s Disease Dementia), to assess the safety and efficacy of SYN120 in patients with Parkinson’s disease dementia (PDD) already treated with a stable dose of a cholinesterase inhibitor.

Past Clinical Trials

BLIND-DATE
The BLIND-DATE trial (“BLINDed Withdrawal of Deprenyl in the DATATOP Extension”) examined the long-term effects of deprenyl on the course of levodopa-treated Parkinson’s disease. (See DATATOP in the Completed Clinical Trials section for the background and details of BLIND-DATE).

CALM-PD
The PSG, under the sponsorship of Pharmacia & Upjohn, Inc. (Kalamazoo, MI), led by Ira Shoulson, MD, and Stanley Fahn, MD, conducted the study, CALM-PD (Comparison of the Agonist Pramipexole versus Levodopa on Motor Complications of Parkinson’s Disease). Enrollment of 301 subjects at 22 sites began in October 1996 and was completed August 1997. This parallel group, double-blind controlled trial is designed to compare the policies of initial treatment with pramipexole versus initial treatment with carbidopa/levodopa in Parkinson’s disease patients. The development of dopaminergic motor complications was the primary outcome of interest. This study also included ß-CIT SPECT measurements, an economic outcome substudy, and a quality-of-life instrument customized for Parkinson’s disease. Subjects were examined prospectively for at least 23.5 months, after which time they had the option of participating in the blinded extension of CALM-PD. Subjects concluded participation in CALMPD and its extension in August, 2001. The results of the CALM-PD study were published in JAMA on October 18, 2000.

DARE
DARE (Dyskinesias And Remacemide Effects), led by Anthony Lang, MD, Stanley Fahn, MD and Ira Shoulson, MD, and sponsored by Astra Pharmaceuticals, was a placebo-controlled study of subjects with Parkinson’s disease who have severe dyskinesias despite optimized antiparkinsonian medications. Enrollment of 39 subjects at five sites began in December 1997 and was completed in May 1998. A report summarizing the preliminary data from RAMP, REAL and DARE entitled “The Glutamate Antagonist Remacemide Improves Motor Performance in Levodopa-Treated Parkinson’s Disease” was presented at the 51st Annual Meeting of the American Academy of Neurology Scientific Session, April 21, 1999, in Toronto, Canada.

DATATOP AND ITS FOLLOW-ON PROTOCOLS
DATATOP (Deprenyl And Tocopherol Antioxidative Therapy OParkinsonism), led by Ira Shoulson, MD, and Stanley Fahn, MD, and sponsored by NINDS, is the largest and longest prospective controlled study of therapeutic interventions in Parkinson’s disease conducted in the world. It was the first of PSG’s multi-center trials. *(Click here to download the complete PDF.)

Evaluation of DOPASCAN™ in Parkinson’s Disease and Related Disorders
PSG, under the leadership of Kenneth Marek, MD, and John Seibyl, MD, and the sponsorship of Guilford Pharmaceuticals, Inc. (Baltimore, MD), conducted a five-center trial to examine DOPASCAN™, a SPECT imaging ligand, as a diagnostic marker for Parkinson’s disease. DOPASCAN™ is a radiotracer that binds to the dopamine transporter and provides a measure of the integrity of dopamine terminals. Enrollment and follow-up of 96 subjects at five sites was completed in December 1996. Data were published in abstract form in Movement Disorders and Journal of Nuclear Medicine and a full report is under review.

ELLDOPA
One of the most lingering and important questions in the therapeutics of PD is whether levodopa, the mainstay of treatment, has long-term beneficial or harmful effects on the progression of disease. A survey on treating patterns was conducted during the PSG/MDS Symposia in October 1995 and reported in October 1996 in Movement Disorders. An application was submitted to the National Institute of Health (NIH) in June 1996 for the ELLDOPA (Earlier versus Later LevoDOPA) placebo-controlled trial, which was reviewed favorably and awarded by the National Institute of Neurological Disorders and Stroke (NINDS-NIH) in January 1998. The ELLDOPA trial, under the direction of Stanley Fahn, MD, and Ira Shoulson, MD, began enrollment of 360 patients with early Parkinson’s disease at 35 PSG sites in October 1998. Subjects were followed for 40 weeks prior to a 17-day washout and final evaluation of the progression of disease. A ß-CIT SPECT study, funded by a grant to Kenneth Marek, MD, by the Department of Defense, was carried out in a sub-set of ELLDOPA subjects to assess a biological marker of the progression of Parkinson’s disease (loss of dopamine transporter binding sites). As of September 2001, enrollment was closed for the study with 361 subjects completing enrollment. The final subject visit is expected in June 2002 with analysis to follow. For additional information on the scientific rationale for this study, please see the 1999 publication in Archives of Neurology.

MOVE-PD (A Phase II Study to Evaluate the Safety and Efficacy of RM-131 in Patients With Parkinson’s Disease & Chronic Constipation)
Status, January 29, 2018: Primary paper published*

The Parkinson Study Group (PSG), under the direction of the MOVE-PD Steering Committee, conducted a clinical trial to test a new treatment for chronic constipation among Parkinson’s disease (PD) patients. Constipation is a common non-motor symptom of PD, which can cause extreme discomfort.

Researchers investigated how individuals with PD and chronic constipation respond to the drug RM-131, as compared to placebo. The study was originally sponsored by Rhythm Pharmaceuticals, Inc. (Boston, Massachusetts) with funding provided by The Michael J. Fox Foundation for Parkinson’s Research. PI: Ronald F. Pfeiffer, M.D.

*( Click here to download the complete PDF.)

For more information regarding this trial visit clinicaltrials.gov.

PATCH I
PATCH I (PArkinson’s Disease Transdermal Clinical Trial Helping to Assess SPM-962 Transdermal System (TDS) in Patients Not Receiving DopaminergicTherapy), led by Ira Shoulson, MD, and under the sponsorship of Schwarz Pharma Inc. (Meguon, WI and Monheim, Germany) conducted a Phase IIb efficacy, safety and tolerability study of the experimental dopamine agonist SPM-962, delivered as a transdermal patch system in patients with Parkinson’s disease who are not receiving dopaminergic therapy. Enrollment of 242 subjects at 28 sites began on November 15, 1999 and was completed in July, 2000.

POETRY
Parkinson’s Disease OEsTrogen Replacement in the Menopause Years. Click here to view the trial record.

PramBID
A randomized, double-blind, active (pramipexole 0.5 mg tid) and placebo controlled, efficacy study of pramipexole, given 0.5 mg and 0.75 mg bid over a 12-week treatment phase in early PD patients. Click here to view the trial record.

PRECEPT
The Parkinson Study Group (PSG), in collaboration with two pharmaceutical companies, Cephalon, Inc. (West Chester, PA) and H. Lundbeck A/S (Valby-Copenhagen, Denmark), conducted a study for patients with early Parkinson’s disease called PRECEPT (Parkinson Research Examination of CEP1348 Trial). The goal of PRECEPT was to determine if the investigational drug CEP-1347 could slow the clinical progression of early Parkinson’s disease. The study assessed the safety and tolerability of different doses of CEP-1347 and also examined the long-term effects of CEP-1347 on the areas of the brain affected by Parkinson’s disease. The study recruited approximately 800 participants at 65 sites across the United States and Canada. Enrollment began in April 2002 and was completed in March 2004.

PRESTO
The Parkinson Study Group (PSG), in collaboration with Teva Clinical Research, Inc., conducted a study for patients with moderate to advanced Parkinson’s Disease called PRESTO (Parkinson’s Resagiline: Efficacy & Safety in the Treatment of “Off”). This 26-week study examined the safety, effectiveness and tolerability of an investigational drug in patients who do not experience full benefit from their L-dopa dosage. The study recruited about 450 subjects at 44 sites across the United States and Canada. Enrollment began in September 2000 and was completed in June 2002.

PRIME
The PRIME (PRamipexole IMinority Persons with Parkinson’s Disease: Efficacy) study led by Caroline Tanner, MD, and Cynthia Comella, MD, and sponsored by Pharmacia & Upjohn, Inc. (Kalamazoo, MI) was a placebo-controlled, safety, efficacy and pharmacokinetic study of pramipexole in minority persons with moderate to advanced Parkinson’s disease who are receiving concomitant carbidopa/levodopa therapy. Enrollment of 144 subjects at 17 sites began in January 1997 and the final subject visit was completed in October 1998. This is the first trial in Parkinson’s disease designed to evaluate the influence of ethnicity on the safety, efficacy and pharmacokinetics of a therapeutic agent.

PROBE
Diagnostic and Prognostic Biomarkers in Parkinson Disease Click here to view the trial record.

PROGENI
Parkinson’s Research: The Organized GENetics Initiative

PSYCLOPS
The PSYCLOPS (PSYchosis and CLOzapine in Parkinson’S Disease) study led by Joseph Friedman, MD, and Christopher Goetz, MD, which examined the effects of the non-neuroleptic, antipsychotic clozapine on dopaminergic-induced psychosis in PD patients, was supported primarily by the FDA Orphan Drug Division. Enrollment of 60 subjects at six PSG sites began in April of 1995 and the final subject visit was completed in January 1997. This randomized, controlled clinical trial supported the findings of multiple open-label studies that low dose clozapine ameliorates psychosis without worsening parkinsonism. The results have been published in abstract form and a full report was in the March 1999 issue of the New England Journal of Medicine, volume 340, pg 757-763.

QE2
QE2 (Coenzyme Q10 Evaluation-2) was a randomized, double-blind, parallel group 16-month study, designed to compare three dosages of coenzyme Q10 (ubiquinone) and placebo in patients who have early PD. Ten PSG sites were selected to enroll 80 subjects. The goals of the study were to: (1) assess a clinical trial design devised to efficiently evaluate the maximally tolerated dose and efficacy of potential protective therapies for PD; (2) extend our previous studies of the safety and tolerability of high doses of coenzyme Q10; and (3) evaluate the ability of coenzyme Q10 to affect the clinical progression of PD and platelet mitochondrial function. Enrollment of 80 subjects was completed in February of 2000.

QE3
(Effects of Coenzyme Q10 in Parkinson Disease) Click here to view the trial record.

March 24, 2014 The primary manuscript for QE3 was accepted and has been published in JAMA Neurology. The abstract and manuscript can be viewed here .

July 27, 2012 The QE3 study was presented at the 16th International Congress of Parkinson’s Disease and Movement Disorders Meeting in Dublin, Ireland in June 2012. An abstract, or a short summary of study results, was presented at the meeting and a copy of the material is available here .

May 27, 2011 The NINDS has stopped the QE3 Phase III study of Coenzyme Q10 for treatment of early Parkinson’s disease acting on the recommendation of the study’s Data Safety Monitoring Board (DSMB).

Quality-of-Life Instrument/Economic Outcomes (PDQUALIF)
Parkinson’s Disease QUAlity of LIFe (PDQUALIF) was a multi-center study to develop and test a quality-of-life instrument specific for Parkinson’s disease. Under the direction of Mickie Welsh, RN, DNS, this study employed a cross-sectional design of individuals in all stages of Parkinson’s disease in an effort to establish the reliability and validity of the PDQUALIF. There were a total of 233 patients enrolled at the participating 13 PSG sites. Analysis compared the PDQUALIF to the SF36 and SIP quality-of-life instruments. An abstract of the preliminary results from Phase II testing was presented at the 1997 PSG/Movement Disorders Society (MDS) Symposia and published in Movement Disorders. In the CALM-PD and TEMPO trials, a modified PDQUALIF scale was used.

RAMP
The RAMP (Remacemide AMonotherapy in Parkinson’s Disease) study, led by Ira Shoulson, MD, and J. Timothy Greenamyre, MD, PhD, and sponsored by Astra Pharmaceuticals was the first placebo-controlled study to evaluate the safety, tolerability and efficacy of dosages of remacemide as monotherapy in patients with early Parkinson’s disease. Enrollment of 200 subjects at 21 PSG sites began in March 1997 and was completed in April 1998.

RAPID
The Parkinson Study Group (PSG), under the sponsorship of Teva Clinical Research, conduced a study for advanced Parkinson’s disease patients with motor complications (“on-off” effects) called RAPID (Rapid-Acting ParkInson’s Drug). This 20-24 week study of TV-1203/Carbidopa dispersible tablets, a novel investigational variation of levodopa, examined the efficacy, safety, and tolerability of TV-1203/Carbidopa dispersible tablets in treating advanced Parkinson disease patients who have motor fluctuations while being treated with chronic levodopa/carbidopa therapy. Teva Clinical Research, based in North Wales, PA is the U.S. affiliate of Teva Pharmaceutical Industries, LTD, Israel, an international pharmaceutical company headquartered in Israel. This study enrolled approximately 300 patients at 41 sites across the United States and Canada and completed enrollment in June 2002.

REAL
REAL (REmacemide as an Adjunct to Levodopa), led by Ira Shoulson, MD, and John Penney, MD, and sponsored by Astra Pharmaceuticals, was the first placebo-controlled study to evaluate the safety, tolerability and efficacy of remacemide in levodopa-treated patients with Parkinson’s disease who have motor fluctuations. Enrollment of 279 subjects at 29 PSG sites began in August 1997 and was completed in June 1998.

ROADS
Follow-up of the 320 subjects in the ROADS (RO 19-6327 Assessment and Dose Finding Study) controlled trial of the MAO-B inhibitor lazabemide, led by Ira Shoulson, MD, and Karl Kieburtz, MD, was completed in 1994 and analysis was completed in 1995. Like deprenyl, lazabemide extended the time before emerging disability required the initiation of levodopa therapy in patients with early Parkinson’s disease. An abstract of the preliminary results of this 18-site investigation of lazabemide in untreated PD patients was presented in May 1995 at the annual meeting of the American Academy of Neurology. A full report was published in Annals of Neurology.

SEESAW
The SEESAW (Safety and Efficacy of Entacapone Study Assessing Wearing-off) controlled trial, led by Ira Shoulson, MD, and Stanley Fahn, MD, and sponsored by Orion-Farmos, Inc. (Espoo, Finland), was initiated in March 1994 to examine the impact of entacapone, a COMT inhibitor, in levodopa-treated PD patients with motor fluctuations. Enrollment of 205 subjects at 18 PSG sites was completed in December 1994, and follow-up was completed in June 1995. A summary of the results of the study was presented at the Fourth International Congress of Movement Disorders meeting in Vienna, Austria, June 1996 (published in Movement Disorders) and the 10th PSG/MDS Symposia in Miami, October 1996 (published in Movement Disorders). A full report of the SEESAW trial was published in Annals of Neurology.

SPIN PD
SPectroscopy IN Diagnosis of PD. Click here to view the trial record.

SPIRAL
The PSG study, led by Karl Kieburtz, MD, and John Nutt, MD, and sponsored by Astra Pharmaceuticals, conducted the study SPIRAL (Study of Pharmacokinetic Interactions Between Remacemide And Levodopa), which was the first study to evaluate whether remacemide, a glutamate receptor antagonist, exerts an effect on circulating plasma levodopa concentrations in patients with Parkinson’s disease. Enrollment of 16 subjects at four sites began in February 1997 and was completed in April 1997. A report has been submitted for publication.

START-LE
START-LE (Short Term Assessment of RO 19-6327 Tolerability in Levodopa Exposed Patients) was the second of the PSG’s trials investigating lazabemide. In this trial, sponsored by Hoffmann-La Roche and led by Ira Shoulson, MD, and Stanley Fahn, MD, 137 subjects being treated with levodopa for their Parkinson’s disease were enrolled at 14 sites from March 1991 to January 1992. This eight-week study demonstrated the overall safety and tolerability of lazabemide in subjects taking levodopa. The primary report of this study was published in Archives of Neurology.

START-UP
Lazabemide (RO 19-6327) is a short-acting, reversible, highly selective inhibitor of monoamine oxidase type B which, unlike deprenyl, is not metabolized to active compounds. The PSG, under the sponsorship of Hoffmann-La Roche, Inc. (Nutley, NJ), and led by Ira Shoulson, MD, and Stanley Fahn, MD, undertook the first of its three trials of lazabemide in the study START-UP (Short Term Assessment of RO 19-6327 Tolerability in Untreated Parkinson’s Disease) from November 1990 to September 1991; 201 subjects with early, untreated PD were enrolled at 14 sites. The overall safety and benefits of lazabemide observed in this eight-week trial justified further long-term investigation of the drug. The primary report of the study was published in Annals of Neurology.

STEADY-PD II
Phase II Safety, Tolerability, and Dose Selection Study of Isradipine as a Potential Disease-Modifying Intervention in Early Parkinson’s Disease (STEADY-PD) was undertaken in subjects with early PD not requiring dopaminergic therapy (dopamine agonists or levodopa) randomized 1:1:1:1 to 5, 10, or 20 mg of isradipine CR or matching placebo daily. The primary outcome was tolerability defined as no more than a 30% difference in the proportion of patients completing the study on the originally assigned dosage between an active and placebo group. If more than one isradipine dosage was tolerable, then a 3-point difference in total Unified Parkinson’s Disease Rating Scale (UPDRS) change between baseline and week 52 (or time to sufficient disability to require dopaminergic therapy) was taken as a criterion for selection of the most desirable dosage for future study. STEADY-PD enrolled 99 subjects. The tolerability of isradipine was dose dependent: placebo, 25 of 26 patients (96%); 5 mg, 19 of 23 patients (83%); 10 mg 19 of 26 patients (73%); and 20 mg 9 of 24 patients (37%). There was no difference in change in UPDRS among dosages. The most common adverse events were peripheral edema (30) and dizziness (24). Isradipine 10 mg daily was the maximal tolerable dosage in this study of early PD. A large placebo-controlled trial will be necessary and is planned to assess efficacy of isradipine 10 mg daily to slow progression of PD disability. *([Click here to download][0] the complete abstract.)

STEP-UP
The STEP-UP (Safety, Tolerability and Efficacy of Pramipexole in Untreated Parkinsonism) controlled trial, led by Ira Shoulson, MD, and Stanley Fahn, MD, and sponsored by Pharmacia & Upjohn, Inc., was initiated in March 1994 to examine multiple dosages of the dopamine agonist pramipexole in early PD. Active follow-up of the 264 enrolled subjects at 20 PSG sites was completed in December 1994. An abstract summarizing the preliminary results of this trial was presented at the PSG/MDS Symposia in Washington, DC, October 1995, and published in Movement Disorders. A full report of the STEP-UP trial was published in the July 9, 1997 issue of the Journal of the American Medical Association.

SURE PD
Safety and Ability to Elevate URate in Early Parkinson Disease. Click here to view the trial record.

TEMPO
TEMPO (Rasagiline Mesylate [TVP-1012] inEarly Monotherapy for POutpatients), led by Ira Shoulson, MD, and Stanley Fahn, MD, is a placebo-controlled multi-center trial, sponsored by Teva Pharmaceutical Industries, Ltd. – Israel and Teva Pharmaceuticals, USA, examining the effects of two dosages of rasagiline in patients with early Parkinson’s disease. Rasagiline is a novel MAO-B inhibitor. Enrollment of approximately 400 patients at 27 PSG sites began in November 1997 and was completed in April of 1999. The results of the TEMPO study were published in Archives of Neurology on December 18, 2002.

TEST-PD/RETEST-PD
The TEST-PD/RETEST-PD (Tolerability and Efficacy of SIB-1508Y Therapy in PD), led by Ira Shoulson, MD and John Growdon, MD, and sponsored by SIBIA Neurosciences, Inc. (La Jolla, CA), is the first placebo-controlled study to evaluate the safety, tolerability and efficacy of dosages of SIB-1508Y in patients with Parkinson’s disease who are requiring, but not receiving, dopaminergic therapy. SIB-1508Y is a nicotinic acetylcholine receptor agonist which produces motor and cognitive benefits in animal models of Parkinson’s disease. Enrollment of 32 subjects at ten sites for the initial phase of the study (TEST-PD, higher dosage groups) began in January 1998 and was completed in May, 1998. Enrollment of 45 subjects for the second phase (RETEST-PD, lower dosage groups) began in July 1998 and was completed in April 1999. The data are currently being analyzed.

Partnering with the PSG

Why partner with the PSG?

OUR PEOPLE

Our members are thought leaders in PD. Your study would be led by a PSG Steering Committee comprised of a study PI and Co-PI, three or four investigators, and a chief biostatistician. We guide you through the clinical trial process from start to finish.

OUR SITES

A streamlined process for site selection with premier credentialed PD centers who are both committed to PD research, and are pre-qualified based on study requirements.

OUR UNIFORM PER SUBJECT FEE

In order to participate all sites must sign off on the uniform per subject fee (decided in partnership by the sponsor and our study budget committee) which eliminates the need to negotiate numerous budgets, saving the sponsor time and money.

OUR FLEXIBILITY

We have two great options for coordination centers or we can work based on the “hybrid model” and credential the CRO of your choosing. We have built-in back up sites ready for immediate activation should a site have to withdraw for any reason. You have access to our administrative services to help with arranging meetings, credentialing sites/investigators, facilitating communication with sites, and assisting in the publication process.

The PSG Advantage

OUR NETWORK

The largest and most experienced network of committed & credentialed PD Centers

OUR COMPREHENSIVE SERVICE AND FLEXIBILITY

Sponsors can select some or all services offered – from protocol creation to FDA application

OUR REPUTATION

Scientific rigor & highest quality publications; greatest impact & longevity; successful FDA application

OUR TRACK RECORD

timeliness and completion of >50 Parkinson studies, with >8,000 enrolled

Clinical Trials 101

Research & Clinical Trials

What is research?

Research is defined by the Department of health and Human Services as a systemic investigation, including research, development, testing and evaluation designed to develop and contribute to generalizable knowledge.

Generalizable

  • Hypothesis is tested
  • Research outcomes are shared
Systemic

  • Defined procedure for data collection process
  • Primary and secondary endpoints are defined prior to data analysis
  • Data is gathered and then analyzed

TYPES OF RESEARCH

Interventional

  • A study that uses an intervention to modify the health of the subjects
  • Administration of a drug or device; medical procedure
  • Manipulation of the environment intended to change the course of a subject’s medical condition

Observational

  • A study without clinical intervention (i.e. survey or questionnaire)
  • An evaluation of patient condition (i.e. PPMI)
  • An assessment of data collected on an individual or group of patients (i.e. PPMI)
Clinical Trials

Sponsor

  • The person, company, or group who wrote the protocol and takes responsibility for the initiation, management, reporting, and document preparation of the trial, as per FDA requirements.

Funder

  • Source of funding to support the conduct of the trial; funding may come from the sponsor or another source.

Human Subjects

  • A human subject is a living individual about whom an investigator obtains data through intervention or interaction or identifiable private information.
  • HIPAA regulations cover research on all human subjects, living or deceased.
  • Identifiable specimens or records of deceased subjects may require approval by the IRB.

Industry Sponsored

  • Protocols for a clinical investigation that are written and initiated by a person or agency outside of the institution
  • The person or agency does not actually conduct the investigation, but pays clinical investigators for their participation
  • The external sponsor takes responsibility for the initiation, management, reporting, and document preparation of the trial

Investigator Sponsored

  • Protocols for a clinical investigation are initiated and conducted by the same person, usually a faculty member
  • Investigator initiated trials carry the same regulatory requirements as industry-sponsored trials, so the investigator takes on ALL sponsor responsibilities
  • Funding sources could be externally funded, grant funded, or unfunded

Grant-funded Clinical

  • A clinical investigation that is funded by the NIH or other granting agencies
  • Subject to further restrictions and requirements that are placed on all federally funded project
  • NIH uses activity codes (e.g. R01, R43, etc.) to differentiate the wide variety of research-related programs they support
Primary Investigator

An individual who actually conducts a clinical investigation, i.e. under whose immediate direction the test article is administered

PI RESPONSIBILITIES

21 CRF 312.60
An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation. An investigator shall, in accordance with the provisions of part 50 of this chapter, obtain the informed consent of each human subject to whom the drug is administered, except as provided in 50.23 or 50.24 of this chapter

21 CRF 812.100
An investigator is responsible for ensuring that an investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations, for protecting the rights, safety, and welfare of subjects under the investigator’s care, and for the control of devices under investigation. An investigator also is responsible for ensuring that informed consent is obtained in accordance with part 50 of this chapter. Additional responsibilities of investigators are described in subpart G.

Eligible to serve as the PI

  • Curators
  • Instructors
  • Librarians
  • Non-tenure-track research and clinical faculty
  • Tenure-track faculty
  • Senior research investigators

Case-by-case Determination

  • Adjunct faculty
  • Visiting faculty
  • Visiting scholars
    Contact the Associate Vice President for Research via email to request permission for such faculty. Please include your CV. If approval is granted, upload the confirmation email as a supporting document into the eIRB+ application.

NOT eligible to server as the PI

  • Postdoctoral fellows
  • Research assistants
  • Graduate students
  • Research associates
  • Undergraduate students

The Clinical Trial Process

Clinical Trials: From concept to Implementation
Pre-Clinical Drug Discovery

Compounds are extracted from natural substances or synthesized in the lab and analyzed for therapeutic value

Pre-clinical testing:

  • Pharmacology
    • Pharmacodynamics
    • Pharmacokinetics
  • Toxicology
  • Animal testing
Pre-Clinical Testing

Pharmacodynamics: the observed effect resulting from a certain drug concentration

Pharmacokinetics: Describes the drug concentration-time courses in body fluids resulting from administration of a certain drug dose

  • Absorption
  • Distribution
  • Metabolism
  • Excretion

Toxicology: Tests the toxicological effects of an agent, including carcinogenicity

Animal Studies: Common animal models for studying compound safety and efficacy include mice, rats, pigs, dogs, and monkeys

Research & Development Statistics

The average cost of R&D for every successful drug is $800,000,000 – $1,000,000,000

For every 5,000-10,000 compounds in the R&D pipeline, 1 receives FDA approval

The Pharmaceutical Research Manufacturers of America (PhRMA) estimates that only 5 in 5,000 compounds that enter pre-clinical testing make it to human testing, and 1 of those 5 might be safe and effective enough to reach pharmacy shelves

Essential Elements of a Protocol

Objectives
Objectives should be clearly stated as a hypothesis to be tested

Background
Sufficient background information should be included so that the rationale for the study is clear

Patient Eligibility Criteria
Inclusion and Exclusion criteria should be explicitly stated

Pharmaceutical Information
Information should include product description, storage requirements, stability, route of administration, and toxicity information

Managing Bias

Controlled Trials

  • Study Drug vs. Placebo
  • Similar Age and Weight
  • Same Stage of Disease

Randomization

  • Subjects are randomly assigned to a specific arm of the study
  • The investigator does not control randomization

Blinding

  • Single Blinding: the patients do not know whether they are receiving study drug or placebo
  • Double Blinding: the patients, investigators, study staff, and data analysts do not know whether they are receiving study drug or placebo

Clinical Trial Blinding

Human behavior is influenced by what we know or believe. In research there is a particular risk of expectation influencing findings, most obviously when there is some subjectivity in assessment, leading to biased results. Blinding (sometimes called masking) is used to try to eliminate such bias.

Double blind: usually refers to keeping study participants, those involved with their management, and those collecting and analyzing clinical data unaware of the assigned treatment, so that they should not be influenced by that knowledge.

Double-Dummy: two active compounds, blinding is possible using this method. For example, if we want to compare two medicines, one presented as green tablets and one as pink capsules, we could also supply green placebo tablets and pink placebo capsules so that both groups of patients would take one green tablet and one pink capsule.

Single blind trials: (where either only the investigator or only the patient is blind to the allocation) are sometimes unavoidable.•Open (non-blind) trials. In trials of different styles of patient management, surgical procedures, or alternative therapies, full blinding is often impossible.

The FDA considers blinded clinical trials ethical if they meet the following criteria:

  • Patients are fully informed of the protocol and treatment options
  • Treatments cannot be denied that could prevent irreversible injury or alter survival
  • ontinuous monitoring looks for negative or positive results
Investigational New Drug (IND)

IND Submission Contents

  • Introductory statement
  • Investigational plan
  • Investigator’s brochure
  • Protocol
  • Pharmacology information
  • Toxicology information
  • Summary of previous experiments
  • Chemistry, manufacturing, and control information
  • Form 1571

When to Submit an IND

  • New indication
  • Significant change in marketing
  • A new route of administration
  • Dosage level change
  • New subject population
  • Changes that significantly increase the risks associated with use of the investigational product

The FDA will notify the PI of approval via formal correspondence containing an IND number and a date of approval. All correspondence and original submission materials should be maintained in the regulatory binder.

Includes information and cautions derived from pre-clinical research

Serves as the official labeling for an investigational drug prior to FDA approval; subsequently, the approved package insert becomes the official labeling

Phase 1
  • Determine Safe Dose Range
  • Toxicity Levels
  • Pharmacodynamics
  • Pharmacokinetics
  • Dose Limiting Toxicity (DLT)
  • Maximum Dose Tolerated (MDT)

OBJECTIVES

  • Determine Safe Dose Range
  • Toxicity Levels
  • Pharmacodynamics
  • Pharmacokinetics
  • Dose Limiting Toxicity (DLT)
  • Maximum Dose Tolerated (MDT)
Phase 2
  • Evaluation of safety and disease treatment effects
  • 100-300 subjects
  • Specific disease condition
  • Continued research regarding safety and less common side effects

OBJECTIVES

  • Determine disease response to study drug
  • Drug-drug interaction
  • Efficacy at various doses
  • Patient Safety
Phase 3
  • Treatment evaluation
  • Thousands of subjects
  • Multi-center design
  • Treatment vs. Placebo
  • Controlled
  • Study intervention compared to or combined with standard treatment

OBJECTIVES

  • Compare study interventions to standard treatment for disease
  • Phase III information used for drug labeling
  • Data is analyzed and findings are submitted to the FDA
New Drug Application
  • Submission requesting FDA approval to market a new drug
  • Review of all pre-clinical and clinical trial data
  • Assess safety and efficacy
  • FDA may audit sites to verify data submitted in the NDA
  • If approved, the drug can be marketed and sold to the public under the FDA guidelines for marketing and distribution
Phase 4
  • Post-marketing studies
  • Long-term safety
  • Affects on different cohorts
    • Dosing
    • Race
    • Gender
  • The sponsor must continue to report Adverse Events (AEs) and finding to the FDA via MedWatch Forms

If dangerous side effects are found, the drug is taken off the market or a Black Box may be added

The Impact of Research

Scientific Research has produced substantial social benefits. It has also posed some troubling ethical problems.

— Belmont Report, 1979

Berlin Code of Ethics: World’s first official regulation of human experimentation, barring non-therapeutic interventions without voluntary consent, as well as experiments on minors and others judged vulnerable or incompetent.

The Nuremberg Code: International code of ethics established in response to inhumane Nazi human experimentation during WWII. The Nuremberg Code established four principles:
▫ Informed Consent
▫ Absence of Coercion
▫ Properly formulated scientific experimentation
▫ Beneficence towards experiment participants

Kefauver-Harris Drug Amendments: Passed to ensure drug efficacy and greater drug safety; drug manufacturers are required to prove to the FDA effectiveness of their products before marketing them and tests for safety during pregnancy are required before a drug can receive approval for sale in the U.S. As a result, the FDA is given closer control over investigational drug studies and FDA inspectors were granted access to additional company records.

Declaration of Helsinki: A statement of ethical principles stating that in medical research on human subjects, considerations related to the wellbeing of the human subject should take precedence over the interests of science and society. This document is widely considered the cornerstone of human research ethics.

The Belmont Report: The National Research Act led to the Belmont Report, which outlined 3 basic principles:
▫ Respect for persons
▫ Beneficence
▫ Justice

International Conference on Harmonization (ICH): Good Clinical Practice (GCP) set as the international standard, providing public assurance that trial subjects are protected.

PRINCIPALS OF THE BELMONT REPORT

Respect for persons: Informed Consent

  • Individuals should be treated as autonomous agents… capable of deliberation about personal goals and of acting under the direction of such deliberation
  • Persons with diminished autonomy are entitled to protection.
  • Requirements to acknowledge autonomy and the requirement to protect those with diminished autonomy.

Beneficence: Benefits in research should outweigh the risks

  • Do not harm the human subject.
  • Maximize possible benefits.
  • Minimize possible harm.

Justice: Equality in selection and opportunity to participate in research

  • Each person should have equal share according to:
    • Individual need
    • Individual effort
    • Societal contribution
    • Merit
Guidelines and Regulations

FEDERAL REGULATIONS

Code of Federal Regulations (CFR):

  • CFR Title 46 Part 46: Outlines federal policy for the protection of human subjects in research, establishing mandates for institutional review boards (IRBs) and additional protections for vulnerable populations.
  • CFT Title 21 Part 50: Specifies that research on human subjects at institutions that hold Federal wide Assurances (FWAs) requires IRB review; this CFR specifies the minimum level of review for different types of research

INTERNATIONAL GUIDANCE

International Conference on Harmonization: Good Clinical Practice (ICH GCP E6)

LOCAL GUIDANCE

Institutional (IRB) versus Central IRB (usually selected by sponsor but can be WIRB, Quorum or others)

Institutional Review Board

The Institutional Review Board (IRB) was established in accordance with federal regulations governing the use of human subjects in research.

The IRB reviews and surveys research to ensure the protection of the rights and welfare of all research subjects.

Investigators cannot initiate or change research protocols until they have received IRB approval.

Good Clinical Practice Training

All faculty or staff listed on a protocol with the IRB must have documentation of training (may be specific requirements at institution)

Required: CITI Web Based Training or other similar program

Required: GCP for Clinical Trials with Investigational Drugs and Medical Devices (U.S. FDA focus) is suitable for individuals proposing to conduct clinical trials of drugs and devices primarily in the U.S. and/or who would prefer a more U.S. FDA-centric curriculum.

Recommended: Clinical Research Coordinator (CRC)CITI Program’s CRC course provides a foundational training specifically focusing on operational and regulatory elements necessary for the ethical conduct of clinical research, while at the same time it is specifically tailored for the needs of clinical research professionals. It offers learners a foundation that expands beyond but is directly connected to theHuman Subjects Research (HSR) andGood Clinical Practice (GCP) ICH training.

Who Can Participate in PSG Trials?

CLINICAL DRUG AND DEVICE TRIALS

For clinical drug and device trials, all site investigators and sub-investigators MUST be credentialed PSG members. A provisionally approved PSG member must provide the name of the site investigator at their institution who will be their “admin SI” while completing their first clinical trial with the PSG.

OBSERVATIONAL AND NON-PHARMACOLOGICAL COGNITIVE OR BEHAVIORAL CLINICAL TRIALS

For observational and non-pharmacological cognitive or behavioral clinical trials, all site investigators must be credentialed. The Primary Investigator of the study will be charged with deciding if sub-I’s must be credentialed as well. Their decision must align with the policies stated in the study protocol.

Those who are approved as “study-specific” site investigators for PSG trials may only work on the study specified in their credentialing approval. Their PSG membership will end at the completion of the study. Should these individuals wish to participate in additional PSG trials, they must re-apply for credentialing with updated documentation.

If a PSG-credentialed SI moves to a new institution that is not a current PSG site, they must inform the PSG Administrative Director and apply for and receive credentialing at their new site before applying for participation in PSG studies.

Coordinators are not required to be credentialed. Their qualifications are taken into consideration during the credentialing of their institution or the PI with whom they are working.