Moh Clinical Research Approval Process. Dr. Ahmad Atif Mirza

MOH clinical research approval process Dr. Ahmad Atif Mirza MRCP Medical and RnD Director, Highnoon Laboratories Ltd., Lahore President, Pakistan Association of Pharmaceutical Physicians

Bahria/HEC Workshop on CR in Life Sciences and the Industrial Implications Islmabad. Nov 7 2007

REGULATORY STEPS OF NEW PRESCRIPTION DRUGS

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Ministry of Health, Drug Control office (MOH-DC) rules and regulations regarding:

Standards to protect rights of clinical trial subjects Standards to assure accuracy & credibility of data & reported results

Good Clinical Practice “Regulations tell you what you are required to do by law.”

“Guidelines tell you the best way to do it”

What Is GCP Anyway? GCP = Good Clinical Practices

This may mean a variety of things to different people…

What Is GCP Anyway? To a physician GCP is following accepted standards of care for a specific disease process To a nurse, GCP is giving good patient care according to nursing standards of care To a principal investigator GCP is following the rules and regulations set forth by the RA/MOH and ICH to govern clinical trials

Definition Word “clinical” is derived from the Greek kline which means bed so the term seems to be related to the “bedside” aspect of the patient/physician relationship. A clinical trial is a type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease.

Features of well-designed clinical trials Clearly stated objectives. Well-defined endpoints or quantifiable measures derived from these objectives. A priori stated decision rules for success or failure of the experimental treatment based on statistical tests involving these endpoints. When necessary, a clearly presented calculation of the sample size and its associated power. Well-described patient inclusion and exclusion criteria, and patient screening and randomization.

Features of well-designed clinical trials A system of data monitoring; this includes:  Safety and efficacy monitoring, possibly by an external body (e.g., a Data Safety Monitoring Board or DSMB), with possibly explicit rules for early study termination.  Data quality monitoring and error correction. All examinations, tests, and evaluations described in detail along with a schedule of when they are to be performed. A data collection system which is based on data collection instruments called Case Report Forms (CRFs) as well as a system of digital data entry.

Why Do Clinical Trials? Evidence-based medicine era 

Objectivity

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Scientific documentation

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Positive significance and relevance

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Negative significance

Evidence-based Medicine 

Finding, analyzing, disseminating and using the very best scientific evidence in combination with clinical expertise to treat patients

Study Design in Clinical Research “There are only a handful of ways to do a study properly but a thousand ways to do it wrong.” Sackett (1986)

Some Fundamental Points No research study stands alone; it must be evaluated along with all available evidence from lab, animal, and other clinical studies. Be careful of over-interpreting results;  ASSOCIATION ≠ CAUSATION The “best” statistical analysis is only as good as the data it’s based on. Continued 

Fundamental Points Flaws in research design are common, and, when present, can completely invalidate the results of any study. A well-designed, properly conducted, randomized clinical trial provides the clearest, most definitive evidence regarding the effectiveness of an intervention.

The Drug Development and Approval Process 1. Early research and preclinical testing 2. IND application filed with RA 3. Clinical trials (phases 1, 2, and 3) 4. NDA filed with RA 5. RA validates claim and approves drug

Phases of Clinical Trials Phase 1: 15-30 people What dosage is safe?  How should treatment be given?  How does treatment affect the body? (ADME) 

Phase 2: Less than 100 people Does treatment do what it is supposed to?  How does treatment affect the body? 

Phases of Clinical Trials Phase 3: From 100 to thousands of people 

Compare new treatment with current standard

Phase 4: From hundreds to thousands of people Usually takes place after drug is approved  Used to further evaluate long-term safety and effectiveness of new treatment 

Protecting Participants Before a Trial Scientific review by sponsoring organization Institutional review board approval Informed consent

Protecting Participants During a Clinical Trial Institutional review boards (IRBs) Data and safety monitoring boards (DSMBs) Minimize risks  Ensure integrity of data  Can stop study if necessary 

Ethics Autonomy (right of patients for self-governance) To exercise this right, a patient must be informed on the benefits and potential risks of the new treatment/procedure (related to the requirement of obtaining informed consent from patients). Beneficence is the patient’s right to be benefited from therapy, and the physician’s duty not to harm the patient. Justice or fairness of distribution of the burdens and benefits of the research. For example, testing on poor people or minorities, and then distributing to the privileged would be in direct violation of this principle.

Ethical Norms of Clinical Trials Sound study designs take into account: Randomization or sharing of risks Proper use of placebo Processes to monitor safety of rx/tx Competent investigators Informed consent Equitable selection of participants Compensation for study related injuries

Ethical Issues: Protection of Human Subjects Rely on integrity of Investigator but outside groups also have oversight Participants’ rights protected by Institutional Review Boards [IRBs] o

An IRB is defined as: "any board, committee or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of biomedical research involving human subjects"

Human Subjects’ Protection IRB responsible for such tasks: Review research to ensure that potential benefits outweigh risks Develop and issue written procedures Review research for risk/benefit analysis & proper protection of subjects Issue written notice of approval/disapproval to the Investigator Review and respond to proposed protocol changes submitted by the Investigator

Human Subjects’ Protection

IRB Responsibilities (continued):

Review reports of deaths, and serious and unexpected adverse events received from the Investigator Conduct periodic continuing review of the study, study risks, selection of subjects, privacy of subjects, confidentiality of data, and the consent process

Informed Consent: A Part of Human Subject Protection Objectives of Informed Consent To Ensure:  Voluntariness  Comprehension  Information To Demonstrate That:  Person freely gave consent to participate  Consent given by a competent person  Person has been given all information  Person knows this is research – not treatment

Components of Informed Consent

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Must Include the Following Information: Why research being done? What researchers want to accomplish What will be done and for how long Risks & benefits of trial Other treatments available Can withdraw from trial whenever desire Compensation for unexpected injuries

REGULATORY STEPS OF NEW PRESCRIPTION DRUGS

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MOH Check List Investigator Brochure Final Protocol Informed Consent (English and Urdu)

GMP Certificate along with the CPP/FSC of COO in case of Phase IV trials. Pre clinical / Clinical data

COA List of Participating Countries Sample of Label Quantity of import on Form 4 along with the sites where trials to be conducted CV's of Investigators Ethics Committee Approval of Sites

Summary of the Protocol

Summary of the IB ( for quick review on drug).

Ethics of Clinical Trials: Protection of Participants 3 ethical principles guide clinical research: Respect for Persons: Treatment of person as autonomous Beneficence: Issue re: potential conflict between good of society vs. individual Justice: Treatment of all fairly & all equally share benefits & risks