New Drug Development

NEW DRUG DEVELOPMENT

In this era of bewildering new drug introduction and rapid attrition of older drugs, the doctor needs to have an overall idea of the manner in which new drugs are developed and marketed. Drug development now is a highly complex, tedious, competitive, costly and commercially risky process. From the synthesis/identification of the molecule to marketing, a new drug takes at least 10 years and costs 500–1000 million US$. The major steps/stages in the development of a new drug are given in the box.

Approaches To Drug Discovery

Natural Sources

Plants are the oldest source of medicines. Clues about these have been obtained from traditional systems of medicine prevalent in various parts of the world; Opium (morphine), Ephedra (ephedrine), Cinchona (quinine), curare (tubocurarine), belladonna (atropine), Quinghaosu (artemisinin) are the outstanding examples. Though animal parts have been used as cures since early times, it was physiological experiments performed in the 19th and early 20th century that led to introduction of some animal products into medicine, e.g. adrenaline, thyroxine, insulin, liver extract, antisera, etc. Few minerals (iron/calcium salts, etc.) are the other natural medicinal substances. The discovery of penicillin (1941) opened the floodgates of a vast source— microorganisms—of a new kind of drugs (antibiotics). The use of microbes for production of vaccines is older than their use to produce antibiotics.

The above natural sources of medicines are by no means exhausted, search for new plant, animal and microbial products as drugs is still a productive approach, especially to serve as lead compounds.

Chemical Synthesis

Synthetic chemistry made its debut in the 19th century and is now the largest source of medicines. Randomly synthesized compounds can be tested for a variety of pharmacological activities. Though some useful drugs (barbiturates, chlorpromazine) have been produced serendipitously by this approach, it has very low probability of hitting at the right activity in the right compound.

A more practical approach is to synthesize chemical congeners of natural products/synthetic compounds with known pharmacological activity in the hope of producing more selective/superior drugs. Many families of clinically useful drugs have been fathered by a lead compound. Often only ‘mee too’ drugs are produced, but sometimes breakthroughs are achieved, e.g. thiazide diuretics from acetazolamide, tricyclic antidepressants from phenothiazines.

Study of several congeners of the lead compound can delineate molecular features responsible for a particular property. Application of this structure activity relationship information has proven useful on many occasions, e.g. selective β₂ agonists (salbutamol) and β blockers (propranolol, etc.) have been produced by modifying the structure of isoprenaline, H₂ blockers by modifying the side chain of histamine, ethinyl-estradiol by introducing a substitution that resists metabolic degradation, mesoprostol (more stable) by esterifying PGE₁.

Many drugs are chiral compounds. Because pharmacological activity depends on three dimensional interaction of drugs with their target biomolecules, the enantiomers (R and S forms or d and l isomers) of chiral drugs differ in biological activity, metabolic degradation, etc. Often only one of the enantiomers is active. Single enantiomer drug could be superior to its recemate, because the additional enantiomer may not only be a ‘silent passenger’ but contribute to side effects, toxicity (dextrodopa is more toxic than levodopa) load on metabolism or even antagonize the active enantiomer. Regulatory authorities in many countries, led by USFDA, have mandated separate investigation of the enantiomers in case the new drug is a chiral molecule. Approval is withheld unless the pure enantiomers are shown to be no better than the recemate. Several drugs, originally introduced as recemates, have now been made available as single enantiomer preparations as well (see box).

Rational Approach

This depends on sound physiological, biochemical, pathological knowledge and identification of specific target for drug action such as H+K+ATPase enzyme or glycoprotein IIa/IIIb receptor. The drug is aimed at mitigating the derangement caused by the disease, e.g. levodopa was tried in parkinsonism based on the finding that the condition resulted from deficiency of dopamine in the striatum. The purine, pyrimidine, folate antimetabolites were introduced in cancer chemotherapy after elucidation of key role of these metabolites in cell proliferation. Because virus directed reverse transcriptase is unique to retroviruses, its inhibitors have been developed as antiHIV drugs. This approach is very attractive but requires a lot of basic research.

Molecular Modelling

Advances in protein chemistry and computer aided elucidation of three dimensional structure of key receptors, enzymes, etc. has permitted designing of targeted compounds, e.g. designing of selective COX2 inhibitors was prompted by the comparative configuration of COX1 and COX2 enzyme molecules. Study of drug binding to mutated receptors and elucidation of configuration of drugreceptor complexes is now guiding production of improved drugs. Attempts are being made to produce individualized drugs according to pharmacogenomic suitability.

Combinatorial Chemistry

Chemical groups are combined in a random manner to yield innumerable compounds and subjected to highthroughput screening on cells, genetically engineered microbes, receptors, enzymes, etc. in robotically controlled automated assay systems. Computerized analysis is used to identify putative drugs which are then subjected to conventional tests. This new approach has vast potentials, but has not achieved major breakthroughs so far.

Biotechnology

Several drugs are now being produced by recombinant DNA technology, e.g. human growth hormone, human insulin, interferon, etc. Some monoclonal and chimeral antibodies have been introduced as drugs.

New molecules, especially antibiotics, regulatory peptides, growth factors, cytokines, etc. produced by biotechnological methods can be evaluated as putative drugs. Other experimental approaches in new drug development are antisense oligonucleotides and gene therapy.

Preclinical Studies

After synthesizing/identifying a prospective compound/series of compounds, it is tested on animals to expose the whole pharmacological profile. Experiments are generally performed on a rodent (mouse, rat, guinea pig, hamster, rabbit) and then on a larger animal (cat, dog, monkey). As the evaluation progresses unfavourable compounds get rejected at each step, so that only a few out of thousands reach the stage when administration to man is considered.

Toxicity tests

The aim is to determine safety of the compound in at least 2 animal species, mostly mouse/rat and dog by oral and parenteral routes.

Acute toxicity: Single escalating doses are given to small groups of animals that are observed for overt effects and mortality for 1–3 days. The dose which kills 50% animals (LD₅₀) is calculated. Organ toxicity is examined by histopathology on all animals.

Subacute toxicity: Repeated doses are given for 2–12 weeks depending on the duration of intended treatment in man. Doses are selected on the basis of ED₅₀ and LD₅₀. Animals are examined for overt effects, food intake, body weight, haematology, etc. and organ toxicity.

Chronic toxicity: The drug is given for 6–12 months and effects are studied as in subacute toxicity. This is generally undertaken concurrently with early clinical trials.

Special longterm toxicity: These tests are generally performed only on drugs which cross phase I clinical trials.

Reproduction and teratogenicity: Effects on spermatogenesis, ovulation, fertility and developing foetus are studied.

Mutagenicity: Ability of the drug to induce genetic damage is assessed in bacteria (Ames test), mammalian cell cultures and in intact rodents.

Carcinogenicity: Drug is given for longterm, even the whole life of the animal and they are watched for development of tumours.

Standardized procedures under ‘Good Laboratory Practices’ (GLP) have been laid down for the conduct of animal experiments, especially toxicity testing.

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) licence. The drug is formulated into a suitable dosage form and clinical trials are conducted in a logical phased manner. To minimize any risk, initially few subjects receive the drug under close supervision. Later, larger numbers are treated with only relevant monitoring. Standards for the 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). Adherence to these provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected. The clinical studies are conventionally divided into 4 phases.

Phase I: Human Pharmacology And Safety

The first human administration of the drug is carried out by qualified clinical pharmacologists/ trained physicians in a setting where all vital functions are monitored and 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 the lowest estimated dose and increasing stepwise to achieve the effective dose. The emphasis is on safety and tolerability, while the purpose is to observe the pharmacodynamic effects in man, and to characterize absorption, distribution, metabolism and excretion. No blinding is done: the study is open label.

Phase II: Therapeutic Exploration And Dose Ranging

This is conducted by physicians who are trained as clinical investigators on 100–400 patients selected according to specific inclusion and exclusion criteria. The primary aim is establishment of therapeutic efficacy, dose range and ceiling effect in a controlled setting. Tolerability and pharmacokinetics are studied as extension of phase I. The study may be blinded or open label and is generally carried out at 2–4 centres.

Phase III: Therapeutic Confirmation/Comparison

Generally these are randomized double blind comparative trials conducted on a larger patient population (500–3000) by several physicians at many centres. The aim is to establish the value of the drug in relation to existing therapy. Safety, tolerability and possible drug interactions are assessed on a wider scale, while additional pharmacokinetic data may be obtained. Indications are finalized and guidelines for therapeutic use are formulated. A ‘new drug application’ (NDA) is submitted to the licencing authority, who if convinced give marketing permission.

Phase IV: Postmarketing Surveillance/Studies

After the drug has been marketed for general use, practicing physicians are identified through whom data are collected on a structured proforma about the efficacy, acceptability and adverse effects of the drug (similar to prescription event monitoring). Patients treated in the normal course form the study population: numbers therefore are much larger. Uncommon/idiosyncratic adverse effects, or those that occur only after longterm use and unsuspected drug interactions are detected at this stage. Patterns of drug utilization and additional indications may emerge from the surveillance data.

Further therapeutic trials involving special groups like children, elderly, pregnant/lactating women, patients with renal/hepatic disease, etc. (which are generally excluded during clinical trials) may be undertaken at this stage. Modified release dosage forms, additional routes of administration, fixed dose drug combinations, etc. may be explored.

As such, many drugs continue their development even after marketing.