S. T. Shanmugapriya, T. Sritha, S. Sumithra, Angayarkanni Thirumalai
Department of Biochemistry, Biotechnology and Bioinformatics, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore- 641 043, Tamil Nadu, India
*Address for Corresponding Author,
Dr. Angayarkanni Thirumalai,
Department of Biochemistry, Biotechnology and Bioinformatics,
Avinashilingam Institute of Home Science and Higher Education for Women, Coimbatore – 641 043, Tamil Nadu, India
Hundreds of pharmaceutical products are currently in development. Developing product should consistent in purity, potency, identity, efficacy and safety. The main goal of drug development is effectiveness and safety. Drug safety and regulation is plays a major role to bring the drug to market and it is also important for FDA and NDA approval. This article is about drug safety, regulation and factors affecting drug safety and regulation.
Keywords: Drug safety, drug regulation, factors affecting drug, efficacy, pharmacokinetics, pharmacodynamics
Introducing a drug into a market is not an easy process; drug development is along process it takes almost 13 years. To release the drug in market needs certain approval based on its safety and efficacy. In pre clinical studies drug should be tested for toxicity (teratogenesis, mutagenesis and carcinogenesis) in animals (through acute, sub acute and chronic) and in clinical studies data should gather a data on drug safety and efficacy based on dosage. A fundamental concept in pharmacology is that a drug must reach the target tissues at sufficient concentration to exert in therapeutic effects without causing significant adverse events. There are certain drug safety and efficacy laws that will be discussed in this review article. Drug response can be impacted by several factors including diet, age, disease, pregnancy, age, weight, lactation, are important biologic variables that can alter the response to drug in particular patients. Drug-drug interaction and genetics also alter the drug response. Individual genetic variation in key gene involved in the metabolism, transport, or drug target can contribute to risk of adverse events or treatment failure. Approval of drug is very important to introduce it in market (Beierle et al., 1999). FDA approval is important to release the drug in the market. FDA (food and drug administration)is dependable for securing the open well being by guaranteeing the security, adequacy and security of human and veterinary drugs, natural items, restorative gadget, our nations nourishment supply, cosmetic, and items transmit radiation. Drug safety is the important aspect of therapeutic treatment that can play a major role in choosing which sedate ought to be given to a understanding. Moreover, considering the concept of advantage we found that drugs with a high risk ought to be avoided unless required. This review focuses on the drug safety regulation and factors affecting drug (Brenner and Stevens, 2013).
The Pure Food and Drug Act of 1906 was the principal government enactment concerning drug item wellbeing and adequacy in the United States. The Act was passed because of the offer of patent meds, regularly by alleged “quack remedy sales reps,” which contained harmful or propensity shaping fixings. The enactment required precise naming of the fixings in drug items and tried to forestall the contaminated of items through the replacement of inert or poisonous elements for the named fixings. Since the Act didn’t direct deceitful promoting, the enactment was just incompletely effective in wiping out dangerous medication items (Brenner and Stevens, 2013).
Reacting to the IOM’s suggestions, the Agency recognized three essential territories of center that would work couple to help an expansive based medication item wellbeing program:
Drug Safety Science: Strengthening the science that underpins the clinical item security framework at each phase of the item life cycle, from pre-market testing and improvement through post promoting observation and danger the executives.
Operations and Management: Improving activities and the executives to guarantee usage of the audit, diagnostic, and correspondence measures expected to fortify the U.S. drug wellbeing framework.
Safety Communications: Expanding and improving correspondence and data stream among all partners occupied with advancing the protected utilization of clinical items.
These central zones, as they proceed to direct and illuminate FDA’s medication wellbeing endeavor, work couple in utilizing resources and conveying benefits through commitments from over the Agency (Center for drug evaluation and research, 2016).
Drug Safety Facts
All medications have results, however the degree of their effect and seriousness shifts from mellow, (for example, gentle tingling or gentle migraine) to extreme, (for example, extreme rash, harm to fundamental organs, principally the liver and kidneys, and potentially even demise). The majority of the results are unsurprising and referenced in the leaf lets for each medication.
In any case, the difficult issue is that a portion of the medications’ results are not recently known or have not been seen, and the genuine danger here is whether they would serious injurious effect on the patients who are utilizing them. Among the elements that may expand the seriousness of the results, the kind of prescriptions and the sort of patients utilizing them are the most important (Gholami and Shalviri, 1999).
A few medications may not cause genuine indications, for example, specific kinds of anti-microbials; different meds may cause genuine side effects, for example, certain disease drugs, hostile to diabetic meds, prescriptions to control raised blood lipids, and numerous others. In any case, genuine antagonistic responses can emerge from broadly utilized and notable prescriptions. For instance, numerous individuals may accept that paracetamol, which is sold as under other business trademarks, is sheltered and would not cause genuine results. Nonetheless, this medication can incite hazardous results at high portions, especially ones influencing the liver. What exacerbates this is the medication is found in numerous blends utilized for cold and influenza and the patient may be uninformed of this and take additional dosages, prompting an immediate liver injury (Larson, 2007; Alshammari, 2014).
Communication Drug Safety
At the time the US Food and Drug Administration (FDA) endorses another physician recommended drug for use in the USA, significant wellbeing issues may stay obscure (Avorn, 2007; Dal Pan, 2012). Pre-endorsement considers, including essential preliminaries, enlist between two or three hundred and a couple thousand patients (Downing et al., 2014). These numbers might be excessively little and the members too homogeneous to even consider identifying uncommon however genuine results or enough recognize increments in unfriendly results over pattern populace rates. When the medication is endorsed, its utilization can grow up to countless patients or more. By then, post-endorsement reconnaissance can reveal beforehand obscure antagonistic occasions (Avorn, 2007), differential reactions between subgroups (Giner et al., 2005), hazardous medication drug associations, and even expanded dangers of death (Van Assche et al., 2005). This new data may require changes to the FDA-endorsed drug name that may incorporate new result profiles or suggested dosing regimens (Lasser et al., 2002).
Specific patient populations and drug safety
The sort of patients utilizing meds is a vital factor in thinking about medications' results. Individuals fluctuate in their reactions to prescriptions as per their age (Crooks and Stevenson, 1981). Also, reactions to drugs shift among guys and females because of the physiological contrasts between sexual orientations (Xie et al., 1997; Beierle et al., 1999; Franconi et al., 2007). Furthermore, there show restraint bunches that need more noteworthy consideration and care when utilizing prescriptions, for example, pregnant ladies, the older, and youngsters (Sannerstedt et al., 1996).
Drug safety and drug – drug and food – drug interactions
Various medicines can co-operations, which can happen with practically all medications. Such collaborations could happen at any stage while the medication is available inside the body. These connections could either decrease or increment the impact of different medications, or could deliver an alternate, new impact. Medication connections can happen in any pharmacokinetic (PK) measure, including ingestion, appropriation, digestion, and discharge. All these PK measures are significant and it is in this way pivotal that patients ought to counsel a doctor or drug specialist about the potential collaborations that may happen among drugs and with specific food sources to maintain a strategic distance from unfortunate impacts (Karch and Lasagna, 1975).
FDA Drug – Regulation activities
FDA post market drug security and viability exercises address parts of medication creation, circulation, and use. This segment features nine exercises that have generally intrigued Congress with regards to connection to sedate security and viability: item uprightness, naming, revealing, observation, drug contemplates, hazard the board, data dispersal, off-name use, and direct-to-purchaser promoting (Bonthagarala, 2017).
Overview of regulatory affairs
During 1950s, different misfortunes for example sulfanilamide solution, antibody misfortune and thalidomide misfortune have brought about generous increment of enactments for drug items quality, security and viability. This has likewise come about into stricter standards for Marketing Authorization (MA) and Good Manufacturing Practices (GMPs) (Bonthargarala, 2017).
Pharmaceutical drug regulatory affairs
This office is answerable for knowing the administrative necessities for getting new items endorsed. They understand what responsibilities the organization has made to the administrative offices where the item has been endorsed. They additionally submit yearly reports and enhancements to the offices. Administrative Affairs commonly speaks with one of the Centers (e.g., Center for Drug Evaluation and Research) at the FDA base camp, instead of the FDA nearby region workplaces. Gimps don't straightforwardly apply to Regulatory Affairs; anyway (Badjataya, 2013), they should comprehend and assess changes to drug assembling and testing exercises to decide whether and when the FDA should be informed.
Regulatory affairs in product management
The vital job of RA proficient is more extensive than enlistment of items, they prompt organizations both deliberately and in fact at the most elevated level. Their job starts directly from improvement of a item to making, promoting and post advertising systems. Their recommendation at all stages both as far as lawful and specialized necessities help organizations save a great deal of time and cash in building up the item and advertising the equivalent. For nations that don't have their on guidelines the World Health Organization rules on wellbeing matters and World Trade Organization on exchange guidelines between countries is followed (Shakeel et al., 2016; Bonthargarala et al., 2017).
Regulatory affairs in clinical trials
The RA proficient is the essential linkbetween the organization and overall administrative offices, for example, US Food and Drug Administration (USFDA and Center for Devices and Radiological Health) Medicines and Healthcare Products Regulatory Agency, United Kingdom, (UKMCA), Therapeutic Goods Administration, Australia European Medicines Agency, Organization of Economic Collaboration and Development (OECD) and Health Canada (Shakeel et al., 2016; Bonthargarala et al., 2017).
Regulatory affairs in R & D
The administrative issues faculty work connected at the hip with promoting and R&D to create, imaginative items that exploit new innovative and administrative advancements to quicken time to advertise. With new items expected to add huge incomes to the organization's main concerns, little abatements so as to showcase compare to huge material increases in income and benefit. Utilizing versatile clinical preliminary systems, getting brisk endorsement from administrative specialists and dodging entanglements in cycles can quicken advancement of new items and help to decrease exorbitant mistakes and delays (Shakeel et al., 2016; Bet al., 2017).
Factors affecting drug safety and efficacy
The main factors which affects the drug safety and efficacy; body weight, age, and pregnancy and lactation.
The average dosage mentioned will be based in mg per kg of body weight. Thus single dose in given between the weight 50-100 kg. Considering this smaller doses will be given to the Indian population as their average weight is 50 kg. However those may not be applicable to the obese, dehydration, edema patients, so careful prescribing of drug is required for the safety and efficacy (Pan et al., 2016)
Pharmacokinetics and pharmocodynamics changes occur on the basis of age. In neonates and elder adults, biotransformation is slow. Renal function also decreases with neonates and elderly than in young adults. The body water content in neonates in high where as in elder adults it is low. So physiologically and metabolically they differ so proper prescription is required. The elder adults are more sensitive to CNS drugs such as neuroleptics, hypnotics, sedatives, respiration represents (Shi and Klotz, 2011; Brenner and Stevens, 2013).
Pregnancy and lactation
Pharmacokinetics of a drug changes between pregnant and non pregnant women. There are many physiological changes that the pregnant women undergo that affects the pharmokinetics of drug. There is slow absorption of drug in pregnant women due to the increase in the progesterone, decrease in gut motility and increase in intestinal motility. Increase in body water up to 8 litre, increase in plasma volume of about 30% and decrease in 0.5-1g% of plasma albumin has been found in pregnancy women. Metabolism is also rapid during pregnancy because the enzymes are induced by increase in progesterone thus increasing the rapid metabolic degradation. Pregnancy is also accompanied by increase in renal flow about 100% and GFR about 70% (Fegali et al., 2015; Satsokar et al., 2015).
FDA has recently updated the labeling system in the heading content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling, which can be called as Pregnancy and lactationlabeling rule(PLLR) eliminating previous categorizing system of such as category A, B, C, D, E and X (Food and Drug Administration, 2014; Food and Drug Administration, 2005).
Drug which is to be administered should be based on the above rule. Some of medications can cause teratogenic conditions in fetus. Analgesic drugs such as paracetomal, allopurinol is considered as safe during pregnancy. Drugs such as warfarin, coumarin are considered unsafe during pregnancy it can cause congenitial malformation (Pem et al., 2016).
Drugs which are unbound to plasma, lipid soluble, poorly protein bound drugs can pass to the breast milk. Drugs such as aspirin, paracetomol, warfarin, heparin, chloromphenicol are considered safe during lactation. Drugs which are contraindicated during lactation includes anticancer drugs, lithium, oral retinoids, iodine, amiodstrone and gold salts (Hotham and Hotham, 2015).
Alshammari TM. 2014. The concept, inception and its importance in patients health. Saudi Pharmaceutical Journal 24(4): 405–412.
Avorn J. 2004. Powerful medicines: the benefits, risks, and costs of prescription drugs. Vintage; Revised, Updated edition, 2005.
Avorn J. 2007. In defense of pharmaco epidemiology: embracing the yin and yang of drug research. The New England Journal of Medicine 357(22): 2219–2221.
Badjatya JK. 2013. Overview of Drug Regulatory Affairs and Regulatory Profession. International Journal Affairs of Drug Regulatory 1(1): 1-4.
Beierle I, Meibohm B, Derendorf H. 1999. Gender differences in pharmacokinetics and pharmacodynamics. International Journal of Clinical Pharmacology and Therapeutics 37(11): 529–547.
Shakeel SM, Basha SS, Nagabhushanam MV, Reddy DN, Bonthagarala B. 2016. Comparision of Regulataory Requirements for Generic Drugs Dossier Submission in United States and Canada. International Journal of Pharmaceutical Science and Health Care 6(6):1-19.
Reddy VS, Mounica NVN, Anusha S, Evangeline L, Nagabhushanam MV, Nagarjunareddy D, Bonthargala B. 2017a. Regulatory Requirements of Similar Biologics for Marketing Autharization in India. International Journal of Drug Regulatory Affairs 5(1): 20-24.
Bonthagarala B, Harsha Y, Reddy VS, Mary D, Nagarjunareddy D, Nagabhushanam M. 2017b. Role of Regulatory Affairs in a Pharmaceutical Industry. International Journal of Pharmaceutical Research and Bio-Science 6(2): 170-177.
Brenner GM, Stevens CW. 2013. Drug development and Safety. Pharmacology. 6th edition. pp.34-43. Reed Elsevier India Pvt. Ltd.
Center for drug evaluation research. 2015 – 2016. Drug safety priorities initiation and innovation. U.S. Food and drug administration.
Crooks J, Stevenson IH. 1981. Drug response in the elderly- sensitivity and pharmacokinetic considerations. Age ageing 10(2): 73-80.
Dal Pan GJ. 2012. Communicating the risks of medicines: Time to Move Forward. Medical Care 50(6):463–465.
Downing NS, Aminawung JA, Shah ND, Krumholz HM, Ross JS. 2014. Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005–2012. JAMA 311(4):368–77.
Fegali M, Venkataramamnan R, Caritis S. 2015. Pharmacokinetics of drugs in pregnancy. Seminars in Perinatology 39(7):512-519.
Food and drug administration. 2005. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/labeling-human-prescription-drug-and-biological-products-implementing-plr-content-and-format
Food and Drug Administration. 2014. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pregnancy-lactation-and-reproductive-potential-labeling-human-prescription-drug-and-biological.
Franconi F, Brunelleschi S, Steardo L, Cuomo V. 2007. Gender differences in drug responses. Pharmacological Research 55(2):81–95.
Gholami KM, Shalviri G. 1999. Factors associated with preventability, predictability, and severity of adverse drug reactions. Annals of Pharmacotherapy 33(2): 236-240.
Giner L, Nichols CM, Zalsman G, Oquendo MA. 2005. Selective serotonin reuptake inhibitors and the risk for suicidality in adolescents: an update. International Journal of Adolescent Medicine and Health 17(3): 211–220.
Hotham N, Hotham E. 2015. Drugs in breast feeding. Australian Prescriber 38:56-59.
Karch FE, Lasagna L. 1975. Adverse drug reactions. A critical review. JAMA 234(12): 1236–1241.
Larson AM. 2007. Acetaminophen hepatotoxicity. Clinics of Liver Disease 11(3): 525-548.
Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. 2002. Timing of new black box warnings and withdrawals for prescription medications. JAMA 287(17):2215–2220.
Pan SD, Zhu LL, Chen M, Xia P, Zhou Q. 2016. Weight-based dosing in medication use; what should we know? Patient Preference and Adherence 10:549-560.
Pem T, Gupta V, Khatik GL. 2016. Safe and Unsafe drug during pregnancy. Journal of Chemical and Pharmaceutical Research 8(3):652-663.
Sannerstedt R, Lundborg P, Danielsson BR, Kihlstrom I, Alvan G, Prame B, Ridley E. 1996. Drugs during pregnancy: an issue of risk classification and information to prescribers. Drug safety 14(2):69–77.
Satoskar RS, Rege NN, Tripathi KR, Bhandarkar SD. 2015. Principles of Drug Prescribing; Factors Modifying the effects of a Drug and Drug Interactions. Pharmocology and Pharmacotherapeutics. 24th edition. pp.129-139. Popular PrakashamPvt Ltd. Mumbai. Reed Elsevier India Pvt. Ltd.
Shi S, Klotz U. 2011. Age – related changes in pharmacokinetics. Current Drug Metabolism, 12(7):601-610.
Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W, Rutgeerts P. 2005. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. The New England Journal of Medicine 353(4):362–368.
Xie CX, Piecoro LT, Wermeling DP. 1997. Gender-related considerations in clinical pharmacology and drug therapeutics. Critical Care Nursing Clinics of North America 9(4): 459–468.