Clincal trails phases

Clinical Trials: Phases

Professor Tarek Tawfik Amin

Epidemiology and Public Health, Faculty of Medicine, Cairo University

Geneva Foundation for Medical Education and Training

Asian Pacific Organization for Cancer Prevention

International Osteoporosis Foundation Wiley Innovative Panel

[email protected] [email protected]

September 2015, Faculty Of Medicine, Cairo University, Cairo, Egypt.

mailto:[email protected]

mailto:[email protected]

05/02/2023 Professor Tarek Amin 2

Clinical Trials• A clinical trial : prospectively

planned experiment for the purpose of evaluating potentially beneficial therapies or treatments

• In general, these studies are conducted under many controlled conditions so that they provide definitive answers to pre-determined, well-defined questions.


Why Clinical Trials?1.Most definitive method to

determine whether a treatment is effective.

• Other designs have more potential biases

• In an uncontrolled setting whether an intervention has made a difference in the outcome?

• Correlation versus causation: The problem of false positive in observational designs


Examples of False Positives: correlation vs. causation

1.High cholesterol diet and rectal cancer2.Smoking and breast cancer3.Vasectomy and prostate cancer4.Red meat and colon cancer5.Red meat and breast cancer6.Drinking water frequently and bladder

cancer7.Not consuming olive oil and breast cancerReplication of observational studies may not

overcome confounding and bias


2. Help determine incidence of side effects and complications.Example: Coronary Drug Project - for patients with documented MI, does taking lipid modifying drugs reduce mortality?

A. Detection of side effect (other arrhythmias)

Clofibrate 33.3%Niacin 32.7% P> 0.05Placebo 28.2%

B. Natural occurring side effect (nausea)Clofibrate 7.6%Placebo 6.2% P > 0.05


3. Theory not always best path

• Intermittent positive pressure breathing (IPPB) reduced use, no benefit

• High [O2] in premature infants Retrolental Fibroplasia, Harmful

• Tonsillectomy Reduced use• Bypass Surgery Restricted use


Examples of clinical trials

• Physicians Health Study (PHS) – risks and benefits of aspirin and beta

carotene in the prevention of cardiovascular disease and cancer

– started recruitment of US male physicians in 1982

– 2x2 factorial structure – Primary endpoint: total mortality– Secondary endpoint: myocardial

infarction


• Eastern Cooperative Oncology Group (ECOG) –multicenter cancer clinical trial–Elderly women with stage II breast

cancer– tamoxifen vs. placebo–Double blind study–primary: tumor

recurrence/relapse, disease-free survival–secondary: total mortality


Placebo Used as a control treatment1. An inert substance made up to

physically resemble a treatment being investigated [sometimes we use active placebo].

2. Best standard of care if “placebo” unethical

3. “Sham control” [performing fake procedures]

Definitions


Adverse event (AE) An incident in which harm resulted to

a person receiving health care. – Examples: Death, irreversible damage to

liver, nausea• Not always easy to specify in advance • May be known adverse effects from

earlier trials• Not necessarily linked to assigned

treatment• Rare AEs may be seen only with very

large numbers of exposed patients and/or long term follow-up: COX II inhibitors (pain reduction vs. cardiovascular AEs)

Definit

ions


Surrogate Endpoints• Variables used to address research

questions often called endpoints• Alternative to desired or ideal clinical

outcomes are Surrogates • Examples– Suppression of arrhythmia (Sudden

death)– T4 cell counts (AIDS or ARC)– Cholesterol (Infarction)

• Used in therapeutic exploratory trials • With caution in confirmatory trials

Definitions

05/02/2023 Professor Tarek Amin

Types of RCTS

Treatment trials.

Preventive trials (vaccine).

Diagnostic or screening tests.

Trials of health care delivery.

Trials of health care policy.


Types of Treatment TrialsPharmaceutical (treatment, prevention, biological, synthetic).Device (prosthesis, sensory aids).Procedure (surgery, laser, radiological).Behavior change (smoking cessation, dietary modification, exercise).Other (counseling, information provision).


Clinical [pharmaceutical] Trials Phases – Phase I

Purpose: Determine basic safety and pharmacological information:

I. Route of administration.II. Safe dosage range.III. Toxicity.IV. PharmacokineticsoTreat: small numbers of patients over short period of time.oUsually no control group.oHealthy adult volunteers or patients who have exhausted all other options (cancer patients) with normally functioning organs.


Clinical Trials Phases – Phase II

Purpose: Evaluate the study drug in patients who suffer from the disease or condition that the drug is proposed to treat:Provide preliminary evaluation of efficacy.Identify group of patients most likely to benefit.Collect additional dosage and safety data. Usually comparison group but not always randomized.


Clinical Trials Phases – Phase III

Purpose: further evaluate the efficacy and safety:

Randomized.⌂ New agent compared to placebo

or current therapy.⌂ Usually multi-center.⌂ Serve as basis for NDA i.e. new

drug application for marketing approval.


Outcomes of Trial Phases

Phase I : maximum tolerated dose.

Phase II : biological effect, adverse events.

Phase III : efficacy, adverse events.

Phase IV : long term effectiveness and safety.


Summary of Phases I-III #Subs . Lengt

hPurpose %Drugs

Successfully Tested

Phase I 20 – 100 Several months

Mainly Safety

70%

Phase II

Up to several

100s

Several months- 2 yrs.

Short term safety; mainly

effectiveness

33%

Phase III

100s – several 1000

1-4 yrs. Safety, dosage &

effectiveness

25-30%


Characterization of Trials

Phase Single Center Multi CenterRandomize

dNon-Rand. Randomize

dNon-Rand.

I Never Yes Never Sometimes

II Rare Yes Yes Sometimes

III Yes Use of Historical Controls

Yes Use of Historical Controls

Carrying out a multi-center randomized clinical trial is the most difficult way to generate scientific information.


• The foundation for the design of controlled experiments established for agricultural experiments

• The need for control groups in clinical studies recognized, but not widely accepted until 1950s

• No comparison groups needed when results dramatic:– Penicillin for pneumococcal pneumonia– Rabies vaccine

• Use of proper control group necessary due to:– Natural history of most diseases– Variability of a patient's response to

intervention

Phase III Trial Designs


Phase III Design• Comparative Studies• Experimental Group vs. Control Group• Establishing a Control

1. Historical2. Concurrent3. Randomized

• Randomized Control Trial (RCT) is the gold standard [Eliminates several sources of bias]


Purpose of Control Group• Allow discrimination of patient

outcomes caused by test treatment from those caused by other factors. –Natural progression of disease–Observer/patient expectations–Other treatment

• Fair comparisons: Necessary to be informative


Goals of Phase III Clinical Trial

• Superiority Trials– A controlled trial may

demonstrate efficacy of the test treatment by showing that it is superior to the control• No treatment• Best standard of care


• Non-Inferiority Trials Controlled trial may

demonstrate efficacy by showing the test treatment is similar in efficacy to a known effective treatment• New treatment cannot be worse by a pre-specified amount• New treatment may not be better than the standard but may have other advantages: Cost, Toxicity and Invasiveness


Name the design and phase of the trial

1- A phase (--) study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30 min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3+3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and 2 patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response.


2- We performed a phase (---) clinical trial to evaluate the efficacy and safety of ledipasvir and sofosbuvir, with or without ribavirin, in patients infected with HCV genotype 3 or 6.

METHODS:We performed an open-label study of 126 patients with HCV genotype 3 or 6 infections at 2 centers in New Zealand, from April 2013 through October 2014. Subjects were assigned 1 of 4 groups that received 12 weeks of treatment. Previously untreated patients with HCV genotype 3 were randomly assigned to groups given fixed-dose combination tablet of ledipasvir-sofosbuvir (n=25), or ledipasvir-sofosbuvir along with ribavirin (n=26). Treatment-experienced patients with HCV genotype 3 (n=50) received ledipasvir-sofosbuvir and ribavirin. Treatment-naïve or -experienced patients with HCV genotype 6 (n=25) received ledipasvir-sofosbuvir. The primary endpoint was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after stopping therapy (SVR12).

RESULTS: Among treatment-naïve genotype 3 patients, 16/25 (64%) receiving ledipasvir-sofosbuvir alone achieved an SVR12, compared with all 26 patients (100%) receiving ledipasvir-sofosbuvir and ribavirin. Among treatment-experienced patients with HCV genotype 3, 41/50 achieved an SVR12 (82%). Among patients with HCV genotype 6, the rate of SVR12 was 96% (24/25 patients). The most common adverse events were headache, upper respiratory infection, and fatigue. One patient with HCV genotype 3 discontinued ledipasvir-sofosbuvir because of an adverse event (diverticular perforation), which was not considered treatment related.

CONCLUSIONS:In an uncontrolled, open-label trial, high rates of SVR12 were achieved by patients with HCV genotype 3 infection who received 12 weeks of ledipasvir-sofosbuvir plus ribavirin, and by patients with HCV genotype 6 infection who received 12 weeks of sofosbuvir-ledipasvir without ribavirin. Current guidelines do not recommend the use of ledipasvir-sofosbuvir, with or without ribavirin, in patients with HCV genotype 3 infection.


3- Bcl-2/IgH-rearrangements can be quantified in follicular lymphoma (FL) from peripheral blood (PB) by PCR. The prognostic value of Bcl-2/IgH levels in FL remains controversial. We therefore prospectively studied PB Bcl-2/IgH levels from 173 first-line FL patients who were consecutively enrolled, randomized and treated within the multicenter phase (---) clinical trial NHL1-2003 comparing bendamustine-rituximab (B-R) with CHOP-rituximab (R-CHOP). From April 2005 to August 2008 783 pre- and post- treatment PB samples were quantified by qPCR. At inclusion 114 patients (66%) tested positive and 59 (34%) were negative for Bcl-2/IgH. High pre-treatment Bcl-2/IgH levels had an adverse effect on PFS compared to intermediate or low levels (high vs. intermediate: HR 4.28, 95% CI 1.70 - 10.77; p=0.002; high vs. low: HR 3.02, 95% CI 1.55 - 5.86; p=0.001). No PFS difference between treatment arms was observed in Bcl-2/IgH-positive patients. A positive post-treatment Bcl-2/IgH status was associated with shorter PFS (8.7 months vs. not reached; HR 3.15, 95% CI 1.51-6.58; p=0.002). By multivariate analysis, the pre-treatment Bcl-2/IgH level was the strongest predictor for PFS. Our data suggest that pre- and post- treatment Bcl-2/IgH levels from PB have

significant prognostic value for PFS in FL receiving first-line immuno-chemotherapy.


4- The authors describe the first mother-infant pair to complete an on-going, prospective, open-label, Phase (---) trial (ALIU) UU3, NCT00418821) determining the safety of laronidase enzyme replacement therapy (ERT) in pregnant women with mucopolysaccharidosis type I (MPS I) and their breastfed infants. The mother, a 32-year-old with attenuated MPS I (Scheie syndrome), received laronidase for three years and continued treatment throughout her second pregnancy and while lactating. A healthy 2.5 kg male was delivered by elective cesarean section at 37 weeks. He was breastfed for three months. No laronidase was detected in breast milk. The infant never developed anti-laronidase IgM antibodies, never had inhibitory antibody activity in a cellular uptake assay, and always had normal urinary glycosaminoglycan (GAG) levels. No drug-related adverse events were reported. At 2.5 years of age, the boy is healthy with normal growth and development. In this first prospectively monitored mother-infant pair, laronidase during pregnancy and breastfeeding was uneventful.


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Clincal trails phases