Drug Development

   

·       Drug - ·       There are various definitions for drug.

·       Any substance that brings about a change in biologic function through its chemical action – Katzung.

·       DRUG DEVELOPMENT PROCESS

The process of new drug development are divided to

1)  Preclinical

2)  clinical

PRECLINICAL STUDY

·       The requirement for preclinical study include adherence to the Good laboratory practice (GLP) for non-clinical studies. These regulations set the minimum basic requirements for: study conduct, Personnel, Facilities, equipment, written protocols, operating procedures, study reports and a system of quality assurance  - to ensure the safety of FDA-regulated product. ·       After preclinical testing à researchers review their findings àdecide whether the drug should be tested in people.

·       The Approaches of identifying new drugs: How new drugs or compound are discovered. Several pathways have been identified which include:

1)  Identify a new drug target.

2)  Rational drug design – via understanding the biologic mechanisms, drug/ drug receptor structure, etc.

3)  Chemical modification of a known molecule.

4)  Screening for biologic activity: natural products etc.

5)  Biotechnology and cloning genes -larger peptides and proteins.

6)  Combination of known drugs: additive or synergistic effects or a repositioning of a known drug for a new therapeutic use.

·       Drug screening

·       This include sequence of experimentation & characterization of the active compound by using different biologic assays at molecular, cellular, organ system, whole animal levels.

·       Pharmacologic profile of drugs are made for example:

o   At Molecular level: study of the compound effect on the Cyp P450 enzyme (liver enzyme)

o   At Cell level: Isolated tissue study is conducted by special equipment in the laboratory and data are gathered.

o   At Systemic disease model: animal models are used to study the effects of the compound on certain parameters. In in vivo study the effects of the compound or drug on the whole system could be characterized. For example,

§  Measurement of blood pressure, heart rate in spontaneous hypertensive rat (SHR)

§  Cardiac effect of the drug in dog.

  

·       Preclinical safety and toxicity testing

·       This stage is very important and the goal of toxicity testing is to try identify all potential human toxicities. Unfortunately this is not feasible most of the time.

·       The researcher need to designing test to further define toxicity mechanisms.

·       The toxicity study also help in predicting the specific and most relevant toxicities to be monitored in human trial.

·       The toxicity testing:

·       Various protocols are used to study the toxicity including:

1)  Acute toxicity: effect of large single dose à lethal dose. Usually 2 species, 2 routes

2)  Subacute toxicity: 3 doses, 2 species, 4 weeks à 3 months

3)  Chronic toxicity: Rodent & non rodent. 6 months or > . Effects of multiple doses (chronic use).

·       The objective in this toxicity testing is to study  

1)  Effect on reproductive performance: teratogenicity & postnatal development. Mating behaviour, reproduction, parturition, progeny, birth defects, post natal.

2)  Carcinogenic potential: 2 years, 2 species

3)  Mutagenic potential: genetic stability and mutations: bacteria, mammalian cell culture.

·       Quantitative estimate

The outcome of the toxicity study include several term including

1)  No effect dose: the maximum dose at which a specified toxic effect is not seen (NAEOL)

2)  Minimum lethal dose: the smallest dose that is observed to kill any animal

3)  Median lethal dose (LD₅₀): the dose that kill approximately 50% of animal.

All these doses are used to calculate initial dose to be used in human

·       Limitation of toxicity testing

Despite best effort made by the researchers, there are limitation in this toxicity study

·       Time : it is time consuming, since the researchers need to the toxic effect in several speciaes over various length of time.

·       Cost: it is expensive because the researchers need to buy the animals, look after them, care and carry out relevant investigations. They require human expertise in handling every stage of this study and need to adhere to certain protocols as outlined by the governing bodies.

·       Ethic: Each study can only be done once ethical approval is granted. The researchers need to justify each and every item or process involved in study. They need to answer why certain types of animal models are used, the number of animals used, how to acre for the animal and even how to sacrifice the animal and most of the time large number of animals required!

·       Limitation of toxicity testing:

Despite their objective and intention, there is limitation in the results of the toxicity testing. Extrapolation of toxicity data from animal to human not completely reliable. Rare adverse effects are Unlikely to be detected, and statistically difficult to prove. One of the example is the Thalidomide disaster

·       Application for clinical trial

Application is made to the governing body once are relevant and required data from the preclinical study have been completed.

EVALUATION IN HUMAN

·       Clinical Trials is done prior to drug marketing. The lead compound need to pass stringent assessment before it can be marketed.Stringent guideline is set by the governing body. Who are involved in human study? Researchers include clinician-scientist, clinical pharmacologist, Statistician and other professionals. Careful design, execution are to be followed.

·       Confounding factors in clinical trials.

· These are outside factors that are not being studied or controlled – but can influence the dependent variable. 

·       The Governing body.   The regulatory body in Malaysia is the MINISTRY OF HEALTH MALAYSIA and the NATIONAL PHARMACEUTICAL CONTROL BUREAU.

·       CRC MOH is the Network of Clinical Research Centres (CRC) that was established in the year 2000.

·       

THE 4 PHASES OF CLINICAL TRIAL

There are some differences in term of the subjects in the study, either healthy volunteers or patients themselves, place of study, numbers of subjects etc.

·       Phase 1-safety & dosage

o   Effects of drug as a function of dosage

o   25-50 healthy volunteers (exception eg. AIDs drugs)

o   Limits of the safe clinical dosage

o   Non-blind trial

o   Detect predictable toxicities

o   Pharmacokinetic studies

o   Done at research centers by trained researchers

o   70% drugs go to next stage

·       Phase 2-efficacy & side effects

o   Subject: patient with target disease

o   n = 100-200

o   Single blind design (inert drug, old effective drug, study drug)

o   Site: special clinical centers e.g. University hospital

o   Broader range toxicities maybe detected

o   33% move to next stage

·       Phase 3: efficacy & monitoring of adverse effect

·       n = up to several thousands

·       Reduce confounding factors by “Double blind” study & cross over study

·       Site: setting similar to ultimate site of use

·       Expensive – large number participants, massive data to analyze

·       Investigators: specialist in diseases studied

·       “rare’ adverse effect e.g. Immunologic – may first be apparent

·       25-30% to next stage

·       Phase 4

·       Is carried out once approval given to market

·       Monitor safety of new drug under actual condition

·       Large number of patients – several thousands volunteer patients

·       Careful and complete monitoring by specialist

·       watch drug induced side effect – which is rare 1 in 10000 or less

·       No fixed duration for monitoring of adverse effect

·       PATENCY APPLICATION

Application for patency  takes around 5 years and the patency period is about 15 years. During this period the researchers and manufacturers have sole rights to produce the new drugs. Legal actions can be taken to those companies that imitate or produce the same drug. After the patency period the new drug then become generic drug

A generic drug: a medication created to be the same as an existing approved brand-name drug (dosage form, safety, strength, route of administration, quality, and performance characteristics). Generic medicines work the same as brand-name medicines

·       “Orphan” Drugs

·       Some drugs such drugs for children diseases or rare diseases are not profitable enough to draw interest  from manufacturers. In order to overcome this problem the USA government under ‘The Orphan Drug Act 1983’ gives special grant to researcher and companies to study and produce them.

As future physician, students need to update their knowledge by reading journals and updates on medication.