Clinical Trials: HISTORY

Dr Urmila M. AswarDepartment of Pharmacology, SIOP, Narhe

• Clinical trials are sets of tests in medical, medical research and drug development that generate safety and efficacy data (information about adverse drug reactions and adverse effects of other treatments) for health interventions (e.g., drugs, diagnostics, devices, therapy protocols).

History of CT before yr 1750

• Persian physician and philosopher, Avicenna• In The Canon of Medicine, he laid down rules

for the experimental use and testing of drugs and wrote a precise guide for practical experimentation in the process of discovering and proving the effectiveness of medical drugs and substances. He laid out the following rules and principles for testing the effectiveness of new drugs and medications.

Earlier rules1. The drug must be free from any extraneous accidental quality.

2. It must be used on a simple, not a composite, disease.

3. The drug must be tested with two contrary types of diseases, because sometimes a drug cures one disease by its essential qualities and another by its accidental ones.

4. The quality of the drug must correspond to the strength of the disease.

5. The time of action must be observed, so that effect and accident are not confused.

6. The effect of the drug must be seen to occur constantly or in many cases, for if this did not happen, it was an accidental effect.

7. The experimentation must be done with the human body, for testing a drug on a lion or a horse might not prove anything about its effect on man.

History

Perhaps the first ever clinical trial was James Lind’s demonstration in 1753 that citrus fruits cured scurvy. He compared the effects of various different acidic substances ranging from vinegar to cider, on groups of sailors, and found that the group who were given oranges and lemons had largely recovered from scurvy after 6 days.

• Before one can initiate testing in human beings, they must conduct extensive pre-clinical or laboratory research.

• Research usually involves years of experiments in animal and human cells.

• If this stage of testing is successful, the sponsor then provides this data to the FDA requesting approval to being testing in humans. This is called an Investigational New Drug Application (IND)

• If approved by the FDA, testing in humans begins. This is done through a formally written and approved protocol.

What is a Protocol?• A study plan on which all clinical trials are based.

• Carefully designed to protect the health of participants

• Describes what types of people may participate in the trial (inclusion and exclusion criteria)

• Gives detailed schedule of tests, procedures, medications, dosages, and length of the study.

• Principal Investigator is responsible for assuring that the protocol is strictly followed for each participant

Randomization of trials

• Researchers assign patients by chance to either a group taking the new diagnostic or treatment agent. Similar to “flipping a coin”.

• Randomization helps avoid bias.

• The assigned groups are often referred to as “arms”.

Example: Patient #1 is assigned to Arm A of the trial, which involves the new modality or treatment.

Patient #2 is assigned to Arm B, which is the standard modality or treatment.

What is a Blinded Study?

• In a single blinded study, the patient does not know which arm of the protocol they have been assigned to.

• This approach avoids bias because when people know what they are taking, it might change the way they react.

Example: Patients who know that they are assigned to the “new treatment” group might expect it to work better and report hopeful signs because they want to believe they

are getting well. This could bias the study by making results look better than they are.

CONT…

• Double blinded studies are those studies where neither the patient or the research physician know whether the patient is receiving the actual study drug or standard drug.

• When no standard is available, some studies compare new drugs with placebo drugs.

• All patients are informed of the possibility of being assigned to the placebo arm of a study

• Patients are “unblinded” only if it becomes medically necessary prior to the end of the study.

Who Sponsors Clinical Trials?

• Physicians• Medical Institutions• Foundations• Voluntary Groups• Pharmaceutical Companies• Federal Agencies (cooperative group

research)– NIH

TYPES of CT

The most commonly performed clinical trials evaluate new drugs, medical devices, biologics, or other interventions on patients in strictly scientifically controlled settings, and are required for regulatory authority approval of new therapies.

Types of CT

• One way of classifying clinical trials is by the way the researchers behave.

• In an observational study, the investigators observe the subjects and measure their outcomes. The researchers do not actively manage the study.

• In an interventional study, the investigators give the research subjects a particular medicine or other intervention. Usually, they compare the treated subjects to subjects who receive no treatment or standard treatment. Then the researchers measure how the subjects' health changes.

Types of CT• NIH organizes trials into 5 different categories.

• Treatment Trials- test experimental treatments, new combinations of drugs, or new approaches to surgery or radiology/radiation therapy.

• Prevention Trials- look for better ways to prevent disease in people who have never had them or prevent them from returning.

• Diagnostic Trials- conducted to find better tests or procedures for diagnosing a particular disease or condition.

• Screening Trials- test the best way to detect certain diseases or health conditions.

• Quality of Life- explore ways to improve comfort and the quality of life for individuals with chronic illness

Phases of Clinical trials

• Pre-clinical • Phase 0 (First in human trials)• Phase 1 (volunteers)• Phase 2 (patients)• Phase 3 (large scale multi-centre)• Phase 4 (post registration

monitoring)

Preclinical evaluation

1. Toxicity Testing2. PKPD3. Pharmacological effects

101

0000

Time required: 1.5-3yrs

IAEC approval

Toxicological studies

• Acute toxicity (Graded dose and 1 or 2 animal species)• Subacute toxicity (3 dose and 2 animal species)• Chronic toxicity (3 dose and 2 animal (1 rodent and other

non rodent)• Special toxicity: i. Effect on reproductive performanceii. Teratogenicityiii. Carcinogenicity (Same dose for 2 yrs)iv. Mutagenicity : AMES Test (S.Typhi, Histidine medium)v. Local toxicity: dermal, ocular, vaginal etc

Pharmacokinetic studies

• Rats, dogs, monkeys• ADME• BA• T1/2

Pharmacological studies

• TI, ED50, LD50 estimation

Human Clinical Trial

• Human ethical committee: 2+5• 2: 1 member secretary, 1 chairman from

outside Institute.• 5: 1 medical doctor, 1 Pharmacologist, 1

socially aware member, 1 lawyer, 1 lay person from society.

• Informed consent: verbal as well as written

Time period: 5-7 yrs

Phase 0

• Conducted in accordance with the United States Food and Drug Administration's (FDA) 2006.

• Microdosing studies• Administration of single sub therapeutic doses• Small number of subjects (10 to 15) • Provides agent's pharmacodynamics

and pharmacokinetics• Companies: go/ no-go decisions

Phase I

• Pharmacologists & employees (25-100 in number) ethical approval

• healthy• informed consent• Medical backup• Monitor• Three different kinds of Phase I trials include:

– SAD-single ascending dose studies– MAD-multiple ascending dose studies– Food Effect-investigates differences in absorption caused

by eating pre-dose

Objectives

• To check whether animal and human show any differences

• Tolerated dose range (Pharmacovigilance),• Pharmacokinetics, Variability between

individuals; effect of route; bioavailability• Indication of therapeutic effects• Indication of side effects

The trial is open labelled and non blind

Single ascending dose studies (SAD)

• SAD those in which small groups (3) of subjects are given a single dose of the drug while they are observed and tested for a period of time.

• If no adverse effects, dose is escalated with 3 new healthy subjects

• If toxicity is obs. then 3 more subjects are given the same dose and if found toxic, the dose is considered as max. tolerated dose (MTD).

Multiple ascending dose (MAD)

• MAD are conducted to understand the pharmacokinetics and pharmacodynamics of multiple doses of the drug.

• A group of patients receives multiple low doses of the drug

• Samples (of blood, and other fluids) are collected at various time points

• Analyzed: How the drug is processed within the body.

Food effects

• A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given.

Phase II

• 150-350 ill people; informed consent

• End point is decided• Maximum monitoring• Often patients where other

treatment failed• Early phase : 200 patients, single

blind • Late Phase: 200-400, controlled

double blind

Once a drug has shown to be safe, then it must be tested for efficacy.This phase may last from several months to two years.Most of these trials are randomized trials

ObjectivesIndication for use; type of patient; severity of disease; dose range, schedule and increment; pharmacokinetic studies in ill people;

Nature of side effects and severity; Effects in special groups.

Phase III

• 1500-3500 ill patients• Multicentre• Randomized• Double blind • More certain data from the objectives of phase 2

studies• Interactions between drugs start to become measurable

in the larger population • Sub-groups start to be established • Special features and problems show up

Single arm trial

• Simplest CT• Only one treatmentWhen drug is studied for the first timeWhen population is homologousWhen there is no other therapy availableWhen placebo is not recommendedEg TD1 to only one group of patient

Parallel group study

• When each of the grp receives a single therapy simultaneously.

• Eg Grp I: tment A• Grp II: tment B or control

Completely Randomized Design

Population

Sample

Randomly assigned

Experimental group

Control group

Independent variable

Treatment A Treatment B

Randomly selected

Two-group simple randomized experimental design04/11/2023 33

Double blind cross over design of Phase III trial

Patient group Week 1 Week 2 Week 3

I SD TD ND

II TD ND SD

III ND SD TD

Factorial design study

• Used when combination of drugs are to be given• Eg in HIV • Eg 3 gps• A: TD1• B:TD2• C:TD1+TD2• D: No tment• Results are difficult to interpret

• Sponsorer can file the application for NDA• Complete Monograph, insert etc

Phase IV

• After approval for marketing• Post Licensing phase• No fixed duration• To find the rare side effects, congenital

effects,drug-drug interactions, safety studies, mortality studies, epidemiological studies.

• PERIODIC SAFETY UPDATE REPORTS• To be submitted by the manufacturer every 6

months for 2 yrs and then annually for next 2 yrs.

The refocoxib story• Rofecoxib , anti-inflammatory drug (NSAID) that has now been

withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea.

• Rofecoxib – FDA-on May 20, 1999, brand names Vioxx, Ceoxx, and Ceeoxx.

• Rofecoxib used widely for arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.

• On September 30, 2004, Merck withdrew rofecoxib from the market

• Increased risk of heart attack and stroke associated with long-term, high-dosage use.

• Merck withdrew but the drug resulted in between 88,000 and 140,000 cases of serious heart disease

• US$2.5 billion in 5 yrs

Time required

S.no Phases Time period {yrs}

1 Drug discovery 2-5

2 Preclinical 1.5-2

3 Clinical 5-7

4 Regulatory 1.5

5 Phase IV 4

Total Approx 20 yrs

Costs Involved

• Omeprazole (anti-gastric acid) £3.5m

• Simvastatin (cholesterol lowering) £2.4m

• Beclomethasone (asthma) £1.8m

• Fluoxetine (antidepressant) £1.5m

• Lansoprazole (anti-gastric acid) £1.4m

• Ranitidine (anti-gastric acid) £1.3m

• Paroxetine (antidepressant) £1.2m

• TOP 7 TOTAL >£13m

Investigational New Drug Application

• Current Federal law requires that a drug be approved for marketing application before it is transported or distributed across state lines.

• But in case of investigational drug, it is required by clinical investigators in many states.

• IND is an exemption.

• FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer) having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system.

Animal Pharmacology and Toxicology Studies

Manufacturing Information

Composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.

Lic form-29 is taken for mfg of new drug

Clinical Protocols and Investigator Information

• Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks.

• Information on the qualifications of clinical trial team.

• Informed consent from the research subjects, • to obtain review of the study by an institutional

review board (IRB), • Adherence to the investigational new drug

regulations.

Review by FDA

• Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials. During this time, FDA (DCGI/CDSCO) has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.

Summary

• An application to conduct clinical trials in India should be submitted along with the data of chemistry, manufacturing, control and animal studies to DCGI. The date regarding the trial protocol, investigator's brochures, and informed consent documents should also be attached. A copy of the application must be submitted to the ethical committee and the clinical trials are conducted only after approval of DCGI and ethical committee. To determine the maximum tolerated dose in humans, adverse reactions, etc.

New Drug Application• The new drug registration (using form no. 44 along with full

pre-clinical and clinical testing information) is applied after the completion of clinical trials.

• The comprehensive information on the marketing status of the drug in other countries is also required other than the information on safety and efficacy.

• The information regarding the prescription, samples and testing protocols, product monograph, labels, and cartons must also be submitted.

• Schedule Y of D&C act, provides the guidelines and requirements for clinical trials.

• The application can be reviewed in a range of about 12- 18 months

• Then the permission is granted.

Regulatory bodies in World

• USA: FDA, Dept of health and human services• Canada: Health Canada• UK: Medicines and Healthcare products

regulatory agency (MHRA)• EU: European Medicines Agency (EMEA)• Japan: Pharmaceutical and Medical Devices

agencies (PMDA)• India:

Regulating bodies in India

• The Drug and Cosmetic Act 1940 and Rules 1945 were passed by the India's parliament to regulate the import, manufacture, distribution and sale of drugs and cosmetics.

• The Central Drugs Standard Control Organization (CDSCO),

• The Drugs Controller General (India) [DCGI] was established.

NDA

Regulatory requirements for clinical trials

Before starting trial• Consent of investigator• Approval by IRB..approval of protocol, site, • Approval from ICMR in case of new molecules

developed in India• Informed consent• Insurance cover for trial related injury

During the conduct

• Compliance with the trial protocol• Reporting protocol violations to EC• Seek approval for protocol amendments• Adherence to GCP• Record all adverse effects• Record of all serious adverse effects to sponsor in 24 hr• Notification of fatal adv effect to RB• Review the progress of results of study• Send periodic status of study.

Post trial requirement

• Site close out• Check investigational product utilization• Analyze the data using statistical softwares• Forward the report from investigator to EC• Seek new drug approval.• Prepare and submit the prescribing

information for ND to the authorities

Newly approved drugs

• Gilotrif (afatinib) Tablets: for lung cancerBoehringer Ingelheim Pharmaceuticals

• Khedezla (desvenlafaxine): for depressionOsmotica Pharmaceutical Corp.