As basic scientists in disease biology, we always strive towards an invention or discovery that can make a positive change in existing clinical scenario. We aim to make the life of at least one patient better. From the molecules appearing before us as signals and bands in our basic science experiments to a practical application in clinics is an immensely long journey.
Drug trials are long tedious and meticulous procedures that ensure efficacy and efficiency of drug formulations before they reach market for public use. The odds of a molecule to reach market as a consumable pharmaceutical preparation are approximately calculated to be one in 5000. It takes an estimated average of twelve years for a molecule to travel the long distance between laboratories to market. Here’s a quick peek into the rigorous grilling a molecule undergoes before it “graduates” to be a marketable medication of clinical acceptance.
Preclinical Evaluation: Once a potential therapeutic molecule is identified by in vitro studies in laboratories, it has to undergo preclinical testing in animals to prove its efficacy as well as to document potential side effects. Such a molecule will be considered for further development only if benefits outweigh risks.
Once the preclinical studies are published in effect and not disproved by peers, the patent holders or their collaborating parties can file an Investigation New Drug Application (INDA) to Food and Drug Administration (FDA). Thirty days are given for FDA to consider the implications of developing the molecule concerned to consumable medication. If FDA does not disapprove or reject the application in thirty days, the applicants can proceed with clinical trials of the drug formulation. The application should specify exactly how the formulation will be prepared, number and inclusion/exclusion criteria of study subjects, expected therapeutic and adverse effects and details of the study design and execution.
Phase 0 Study: Before clinical trials begin, a Phase 0 study is carried out to study the pharmacological properties of drug formulation. 10-15 healthy volunteers are given subtherapeutic doses of the formulation to titrate optimum dosage depending on absorption, distribution, metabolism and clearance of the chemical in human body.
Phase I Trials: Once the IND is approved by FDA, applicant parties by themselves or in collaboration with pharmaceutical industry and clinicians can start using the drug formulation on less than eighty healthy volunteers to document in detail potential adverse effects. This is called the Phase I trial, when drug dosage, safe therapeutic window, effective route of administration etc are fine tuned. Moreover, this period is also utilized to study the pharmacokinetics and dynamics including distribution, storage, metabolism, clearance, duration of effect, half life etc. The execution of study and analysis of results may take up to twelve months usually.
Phase II Trials: Once Phase I trials provide favorable results; the formulation can be used in patients with disease for which the drug is intended. This study requires data analytics from about one to three hundred patients. Lasting for about eighteen to twenty four months, these studies look into the dosing of drug formulation in detail. Precise values of minimum and maximum dosages are determined, thus validating a strict therapeutic window of safety. The efficacy of the drug in humans is studied for the first time at this point. An expert team of molecular biologists, biochemists, biostatisticians, pharmacologists and clinicians are directly involved at this stage of the trial. The study is carried out under extremely controlled settings to contain unforeseen adverse effect.
Phase III Trials: Another thirty six to forty eight months are spent to determine therapeutic benefits and potential side effects of the formulation. A randomized controlled study involving multiple hospitals, clinicians, Institutional Ethical Bodies and medical lawyers is carried out to collect data from nearly 3000 patients as test and control subjects to document effects of the drug. Efficiency of the drug formulation to manage targeted pathology is studied at a community level at this point. Equal or perhaps, more attention is given to find out any potential side effects previously undocumented during Phase II trials. The study results should be published in peer-reviewed journals with no conflict of interests of involved parties as well as no dispute from experts in relevant fields. These results also serve as a basis for FDA to analyze risk versus benefits of the drug formulation.
Once Phase III trials show promising results, the involved parties, usually drug manufacturing pharmaceutical giants at this point, file a New Drug Application (NDA) to FDA with data regarding the drug formulation available till date. A typical NDA may easily go from 100,000 to 150,000 pages. Expert committee formed by FDA will then analyze the application unbiased. An estimated time of thirty months is needed for FDA to meticulously analyze all the aspects of the new drug formulation as this goes into market for widespread use across multiple communities once approved at this point. Unlike clinical trials under controlled settings, the usage of a drug at community level cannot be steered or supervised. Needless to say, extreme caution is therefore taken before formally approving the drug to be produced in large scale for clinical use.
Phase IV Trials; Even after reaching market, a drug is not dispensed completely uncontrolled. Post-marketing Surveillance, also called Phase IV trials are carried out strictly for up to twenty four months and leniently during the entire lifetime of the drug’s medical use to document therapeutic and adverse consequences of the drug formulation at a community level. At this point, the drug is available only as its original formulation, manufactured and marketed only by the party holding patent and FDA approval. One can easily understand why non-generic drugs are expensive as the patent holding drug manufacturer is trying to win back all its expenses of research and development of the formulation as well as the exuberant expenses of conducting multiple phases of drug trials. Drug developers are given patent protection of an original formulation for twenty years in most of the countries. Under special circumstances, a patent term restoration can be given for an additional five years if manufacturers convince FDA for an extended period for clinical data evaluation. This is the period during which manufacturers market the drugs as a brand and earn their invested capital back. This period is also infamously regarded as the period of huge profits for the manufacturer due to their monopoly in markets.
After the patent protected period, other pharmaceutical companies can file an Abbreviated New Drug Application (ANDA) to FDA demonstrating therapeutic equivalence of their formulation to the original brand product. If approved by FDA, the new formulation will be added to Approved Drug Products with Therapeutics Equivalence Evaluations list. This is endearingly called The Orange Book. This is the official approval for the applicant to manufacture and market its formulation as generic drugs. As the capital investment involved in such drug development is much less, generic drugs bring down the price of drugs by about thirty to eighty percent of that of original brand. Moreover, as more manufacturers get bioequivalence approval for their formulation, competition in markets will get stronger, thus forcing companies to slash their prices to sustain demand. This is one noble reason why good quality medications are available even to countries with poor economy without having to sweat much on pharmaceutical research and development.