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NEW DRUG DEVELOPMENT
PRESENTED BY- DR. RAJESH.
A. KAMTANE, 2nd YEAR PG
DEPARTMENT OF
PHARMACOLOGY,
MIMS, HYDERABAD
From the synthesis /identification of the molecule to its marketing, a new drug takes at least 10 years and costs 500-1000 million US$.
New drug development is done as per the guidelines laid down by Schedule Y of Drugs and Cosmetics Act (10th amendment)2001, which were amended later in 2005.
STAGES IN NEW DRUG DEVELOPMENT
1.Synthesis / isolation of compound : (1-2 years)
2. Preclinical studies : (2-4 years)
3. Scrutiny and grant of permission for clinical trials : (3-6 months)
4. Pharmaceutical formulation, standardization of chemical / biological / immuno-assay of the compound : (0.5-1 year)
5. Clinical studies : phase 1, 2, 3 and long term animal toxicity testing : (3-10 years)
6. Review and grant of marketing permission : (0.5-2 years)
7. Post marketing surveillance : (phase 4 studies)
Is it safe? Does it work?
Does it work in double blind trials?
Drug development process can be divided into 3 main phases-
1.Drug discovery phase- during which candidate molecules are chosen on the basis of their pharmacological properties.
2.Preclinical phase- during which wide range of animal studies are performed.
3.Clinical trial phase- during which the lead compound is evaluated for safety and efficacy in human volunteers and patients.
Drug Discovery Phase
Most new drugs are discovered and identified through one of the following approaches-
1.Random Screening-
It is a sort of blind hitting procedure where new chemical entities (natural or synthetic) are subjected to series of pharmacological screening procedures to explore different types of biological activity.
Such tests include studies on animal behaviour, animal models of the human diseases and on isolated tissues.
Although these approaches are time consuming, expensive and inefficient in providing fruitful results, sometimes these are valuable, since many drugs like morphine, atropine, digitalis, quinidine were discovered in this way.
Cyclosporine, an immunosuppressant drug was also
discovered during routine screening of fungal products.
Natural Compound Collections
Natural Compound Library Screening
2. Serendipity (happy observation, by chance)
•Sometimes a new use is discovered for an old drug or its side effect finds a new therapeutic application.
Examples-
1. Penicillin was discovered in this way, which started the beginning of antibiotic therapy.
2. Lignocaine (local anaesthetic) and phenytoin (antiepileptic) were later used as antiarrhythmics .
3. Methotrexate, an anticancer drug, is also used for psoriasis.
4. Cyclophosphamide and azathioprine (both cytotoxic drugs) are also used to prevent tissue rejection in kidney transplant.
3. Rational drug designing-
•Two basic strategies are used in rational drug designing---compound-centered approach and target-centered approach.
•Promising agents, through compound-centered approach, could be obtained from natural products. E.g. penicillin from penicillium notatum, paclitaxel (anticancer drug) derived from Pacific yew tree, cyclosporine (immunosuppressive drug) obtained from fungus.
•The main disadvantage in obtaining lead products from natural source is that these are often complex molecules which are difficult to be synthesized. It is ultimately difficult to synthesize their modified analogues also. Hence lead optimization becomes difficult.
•Compound centered drug designing can be followed for synthetic products also.
•Drugs can be developed from pharmacological data obtained from structure activity relationship of an established drug. E.g.--- many beta blocking drugs available today are based on propranolol structure, --- many ‘triptans’ are based on structure of sumatriptan.
Target-centered approach---
•Biochemical or molecular targets are used to search for promising compounds.
•Example—it was known that inhibition of angiotensin-converting enzyme (ACE) blocks conversion of angiotensin 1 to angiotensin 2 and hence lowers the blood pressure. Hence it made sense to look for ACE inhibitors (ramipril, lisinopril, etc) or for angiotensin 2 receptor antagonists (losartan, candesartan, telmisartan) as useful antihypertensives.
•With this approach, there is high possibility of getting useful promising agents for lead optimisation.
4. Designing of a prodrug or an active metabolite as a drug-
•Prodrug- e.g. levodopa used in treatment of parkinsonism.
•Active metabolite- e.g---Paracetamol, an active metabolite of phenacetin, was introduced as a safe analgesic this way. ---Similarly, active metabolite of procainamide, N- acetyl procainamide, is an effective antiarrhythmic drug which does not cause lupus-like syndrome that occurs with procainamide.
•After the synthesis or isolation of compound, their purity is ascertained by physico-chemical and analytical studies.
•Next comes the stage of LEAD OPTIMISATION where the aim is to identify one or two drug candidates suitable for further investigation.
•Three to five years may be spent to come to this stage.
•The promising LEAD COMPOUND is then subjected to preclinical evaluation.
•The clinical trials follow only when the results of preclinical evaluations are encouraging.
PRECLINICAL STUDIES
PRECLINICAL EVALUATION PHASE(ANIMAL STUDIES)
•After synthesizing / identifying a prospective compound, it is tested on animals to expose the whole pharmacological profile.
•Experiments are generally performed on a rodent (rat, rabbit, mouse, guinea pig, hamster) and then on a larger animal (cat, donkey, monkey).
•As the evaluation progresses, unfavorable compounds get rejected at each step, so that only a few out of thousands reach the stage when administration to humans is considered.
Objectives of animal studies are to evaluate---
1.Activity
2.Toxicity
3.Selectivity and Specificity
4.Mechanism of action
5.Drug metabolism
•The following types of studies are performed---
1.Pharmacodynamic Studies---
•Here actions relevant to the proposed therapeutic use (and other effects) are studied on animals.
•For e.g., antihypertensive activity of the lead compound on dogs, cats or rats to find out blood pressure changes and other cardiac effects like ECG changes, etc.
2. Tests on isolated organs, bacterial cultures,etc---performed to detect specific activity, such as antihistaminic, antisecretory, antibacterial, etc.
3. Tests on animal models of human diseases---such as spontaneously (genetically) hypertensive rats, alloxan induced diabetes in rat or dog, etc.
4. General observational test---The drug is injected in tripling doses to small groups of mice which are observed for overt effects. Preliminary clues are drawn from the profile of effects observed.
5. Confirmatory tests and analogous activities---Compounds found active are taken up for detailed study. Other related activities. e.g antipyretic and anti-inflammatory activity in an analgesic are tested.
6. Mechanism of action---attempts are made to find out the mechanism of action, e.g. whether an antihypertensive is an alpha blocker or beta blocker, etc.
7. Systemic pharmacology---irrespective of the primary action of drug, its effects on major organ systems such as CNS, CVS, RS, GIT are worked out.
8. Quantitative tests---the dose-response relationship, maximal effect and comparative efficacy with existing drug is ascertained.
9. Toxicological studies---•Aim – to determine safety of the compound in at least 2 animal species, mostly mouse/rat and dog by oral and parenteral route.
•Types of toxicity studies are-
(1) Acute toxicity- Aim is to find out the acute dose that is lethal to 50% of the animals (LD 50).
Organ toxicity is examined byhistopathology on all animals.
2. Subacute toxicity-
Aim is to identify the target organs susceptible to drug toxicity.
The animals are maintained at the maximum tolerated doses for a period of 1-3 months so as to allow development of pathological changes.
Finally, animals are killed and subjected to histopathological examination.
3. Chronic toxicity-
Such studies are important if the drug is intended for chronic use in human beings.
The duration of study may range from one to two years.
These studies may also run simultaneously with clinical trials, to cut short the time factor.
10. Pharmacokinetic studies-Done after toxicological studies.Information is obtained for its pharmacokinetic parameters (ADME, Vd, BA, t1/2)
11. Special long term toxicity-these tests are generally performed only on drugs which cross phase 1 clinical trials.
12. Reproduction and teratogenecity-effects on spermatogenesis, ovulation, fertility and developing foetus are studied.
13. Mutagenecity-ability of the drug to induce genetic damage is assessed in bacteria (Ames test), mammalian cell cultures and in intact rodents.
14. Carcinogenecity-drug is given for long term, even the whole life of the animal and they are watched for development of tumours.
Standardizied procedures under ‘Good Laboratory Practices’ (GLP) are laid down for conduct of animal experiments, especially toxicity studies.
Assessment of Safety Index-
Therapeutic index
Maximum Tolerated Dose (MTD),
No Observable Adverse Effects Level (NOAEL),
No Observable Effects Level (NOEL) and
Human Equivalent Dose (HED) are determined in species similar to humans (like monkeys), finally to calculate First in Human Dose (FIH) which will be latter used in phase 1 clinical trials.
FIH is 1/5 or 1/10th of HED.
CLINICAL TRIALS
Ethics Committees
• The ethics committee reviews a protocol before the study is allowed to start. Their job is to ensure that the risks of being in the study are not greater than the potential benefit.
IRB( Institutional Review Board) IEC (Independent Ethical Committee)
• To ensure the rights and welfare of the participants.
• FDA regulations mandates to review the clinical trial protocols for ethical and legal issues.
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IRB
The investigator must furnish the IRB with the following documents for review and approval:
• Trial Protocol• Written Informed Consent Forms• Written Information for Subjects (Advertisements)• Information about compensation to patients• Investigator Brochure• Available (or additional) Safety Information• Investigator’s CV• All amendments to study protocol
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IRB
The IRB’s possible responses:• approval or favorable opinion• modifications required for approval• disapproval or negative opinion• withdrawal or suspension of an earlier approval
No subjects should be enrolled until the IRB has issued an approval (21 CFR §56.109)
Informed Consent
• Eight basic elements of informed consent (21 CFR § 50.25)
1. Trial involves research, purpose of the research
2. A description of any reasonably foreseeable risks or discomforts
3. A description of any benefits to the subject which may reasonable be expected from the research
4. A disclosure of appropriate alternative procedures or treatment that may be available to the subject
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Informed Consent
5. A statement describing the extent to which confidentiality of records identifying the subject will be maintained.
6. An explanation as to whether any compensation and whether any medical treatments are available if injury occurs.
7. An explanation of whom to contact for answers to questions about the research and research subjects’ rights .
8. A statement that participation is voluntary
Clinical Trials & Research 38
Informed Consent
• Participation in clinical trials is always voluntary.
No, thank you, I’d rather not participate.
Yes, I would like to
participate.
Clinical Trials & Research 39
Informed Consent• Purpose
• Medicine to be studied
• Procedures and schedule
• Risks
• Potential benefits
• Alternatives to participation
• Confidentiality
Clinical Trials & Research 40
What is a Clinical Trial?Identify a health question.
Develop a plan.
Enroll volunteers and follow the plan.
Study the information collected.
Share the results with others.
Improve treatment.
Objectives of a clinical trial are to establish---
1.Safety
2.Efficacy
3.Therapeutic conformation in a large population.
4.Drug metabolism in humans.
5.Unpredicted adverse reactions and new therapeutic applications during wide use in the community.
CLINICAL TRIALS-
•When a compound deserving trial in man is identified by animal studies, the regulatory authorities are approached who on satisfaction issue an ‘investigational new drug’ (IND) license.
•The drug is formulated into a suitable dosage form and clinical trials are conducted in a phased manner.
•Standards for design, ethics, conduct, monitoring, auditing, recording and analyzing data and reporting of clinical trials have been laid down in the form of ‘Good Clinical Practice’ (GCP) guidelines by an International Conference on Harmonization (ICH) and Declaration of Helsinki.
NAZI HUMAN EXPERIMENTS
Declaration of Helsinki-1964
1.The clinical trial must minimize the risk for participants.
2.Provision for care of the patients.
3.Terminate the trial when the risk becomes incompatible with the goals of the trial.
4.Adverse events to be reported immediately to an ethical committee
Clinical Trials & Research 46
Phases of Clinical Trials
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Phase 0 Clinical trials
Known asHuman Micro dosing.
To confirm whether the drug behaves in human subject as was expected from pre clinical studies.
Phase 0 Clinical trials
Single sub therapeutic doses of the study drug is given to a small number of subjects ( 10 to 15 ).
Purpose is to gather preliminary data on best PK and PD parameters in humans to take forward for further development.
It gives no data on Safety or Efficacy.
The clinical studies are conventionally divided into 4 phases-
Phase 1: Human pharmacology and Safety.The objectives of this phase are---
1.To check for safety and tolerability .
2.To determine the pharmacokinetics of the drug in humans.
3.To determine a safe clinical dosage range in humans.
The common rule is to begin with 1/5th or 1/10th of
the maximum tolerated dose (mg/kg) in animals
and calculating it for an average human body weight
of 70 kg. The drug is then given in small increments till
the therapeutically effective dose is attained by clinical
observation.
Phase 1 trial is carried out by qualified clinical pharmacologists/ trained physicians in a setting where all emergency/ resuscitative facilities are available.
Subjects (mostly healthy volunteers, sometimes patients) are exposed to the drug one by one (total 20-40 subjects) , starting with lowest estimated dose and increasing stepwise to achieve the effective dose.
No blinding is done: the study is open label. i.e. both, the investigator and the subjects know what is being given.
Phase 2: Therapeutic exploration and dose ranging-
•In this phase, the drug is studied for the first time in patients with target disease, to determine its efficacy.
•The main purpose is to decide an end point.
e.g. •pain relief is the end point for testing an analgesic. •reduction in tumour size for anticancer drugs.
•The study is generally carried out at 2-4 centers.
•Phase 2 can be single or double blind study.
•Such studies are mainly conducted in two ways-
a.Parallel design---
One group receives the new drug under trial while other group receives control (established drug) or placebo.
Then results in one group are compared with those in other group.
b. Crossover design---
Here the new drug is alternated with control (established drug or placebo) in the same patient.
In this method, patient acts as his own control.
This reduces the chances of erroneous results due to individual variation amongst the patients.
Phase 3: Therapeutic Conformation/ Comparison-
•Generally these are randomized, double blind comparative, controlled clinical trials.
•Conducted on a larger patient population (500-3000) by several physicians at many centers.
•Here new drug is compared with previously established drug or placebo, under standardized conditions.
•Safety, tolerability, and possible drug interactions are assessed on a wider scale.
•Indications are finalized and guidelines for therapeutic use are formulated.
•A ‘new drug application’ (NDA) is submitted to the licensing authority, who if convinced gives marketing permission, with ‘New Drug Status’
Launch the drug
Phase 4Drug is placed in the market and patients are monitored for side effects.
Phase 4: Postmarketing surveillance-
•In phase 4, data on safety, efficacy and tolerability is collected from practicing physicians.
•Uncommon/ idiosyncratic adverse effects and unsuspected drug interactions are detected at this stage.
•Additional indications may emerge from surveillance data.
•The phase 4 has no fixed duration as it is the surveillance phase.
•During the ‘New Drug Status’, the manufacturer is expected to report any new information about the drug concerning its safety.
•Such Periodic Safety Update Report (PSUR) is to be submitted every six months for first 2 years and then annually for the next 2 years.
•The drug may remain in ‘New Drug Status’ for several years until the Drug Control authorities are confident about its release to unrestricted marketing.
•Further therapeutic trials involving special groups like children, elderly, pregnant, lactating women, patients with renal/ hepatic diseases, etc (which are generally excluded during clinical trials) may be undertaken at this stage.
