Table of Contents
Drug development is a complex and time-consuming process from initial discovery through clinical trials and regulatory approval, including drug discovery, lead compound discovery, preclinical research, new drug clinical trial application, clinical research, etc., and the research and development of new drugs require a lot of investment human, material and financial resources.
This article will focus on factors that hinder drug development and launch and how to overcome them:
What are the difficulties in drug development and marketing?
(1) Research and development are challenging: developing a new drug requires extensive research and development. An in-depth understanding of the underlying disease mechanism and the coupling between the drug and the biological system is challenging.
(2) Safety concerns: Safety is essential to drug development. Researchers must ensure the drug is safe and not cause adverse reactions or toxicity. The drug development requires extensive preclinical testing and clinical trials, which may take years to complete.
(3) Intellectual property protection: The research and development of drugs involves many patents and technical secrets. If the corresponding intellectual property protection cannot be obtained, conducting research and development work will be easy.
(4) Regulatory requirements: Drug development is strictly regulated by NMPA, FDA, EMA, and other agencies.
(5) Drug R&D costs and professional technical personnel: Drug development and the cost of developing a new drug is high. This can be a significant hurdle for smaller biotech companies or academic researchers. Biomedical research and development also require a large number of specialized talents.
(6) Uncertainty: There is a high degree of uncertainty in drug development, and many drugs fail in preclinical or clinical trials. This could result in significant financial losses for drug developers and investors, such as insufficient clinical trial data, improper selection of test subjects, etc., which may also hinder the launch of drugs.
(7) Policy environment: The quality of the policy environment will have a meaningful impact on the development and marketing of drugs. For example, the drug approval system and medical insurance policy will affect drug development and marketing.
(8) Market demand problem: After launching the drug, it must face fierce market competition. If the market demand is sufficient, it will be easier for the drug to succeed.
Early patient, access to established and new medicines is a significant public health concern in settings with limited regulatory resources. It is common for countries to require in-country efficacy or bioequivalence studies before marketing authorization, often delaying the launch of these products by years.
Requirements for domestic trials are sometimes scientifically justified; however, these requests are often based solely on tradition, legal conditions, or political factors, which may include financial incentives associated with trials.
As the pace of drug discovery has increased, so has the cost of these drugs. The Patented Medicines Price Review Board (PMPRB) published a report in 2020 describing changes in the cost of cancer drugs over the past decade. The information related that annual spending on cancer drugs tripled to $3.9 billion in 2019, accounting for 14.6% of the drug market, compared to 7.1% in 2009.
Many people think that there are financial reasons for the delay. Still, many factors within a country can affect a drug’s pharmacokinetics (PK) and pharmacodynamics.
Internal Factors - Disease Prevalence and Microbial Genetic Diversity
Disease prevalence can vary significantly across regions and lead to significant differences in drug use. Examples include the widespread use of antimalarial drugs in the tropics and the increasing use of antidiabetic medications in South Asia. Any important regional variables affecting disease mechanisms and pharmacology in the relevant population should be considered before making a drug available in a country.
The prevalence of hepatitis C virus (HCV) varies globally and is complicated by the high genetic diversity of HCV. Regional differences in genotype prevalence and the corresponding treatment responses of different HCV genotypes underscore the impact of HCV diversity.
Leishmania etiology is complicated by 20 pathogenic bacteria distributed worldwide that manifest in four different clinical presentations. Still, the newly approved label for milter specifies only a limited number of these bacteria species, leading to treatment resistance. Pathogen-specific therapeutic interventions are not isolated to HCV and leishmaniasis infections. Still, they are common in other diseases such as malaria, human immunodeficiency virus infection, and tuberculosis, illustrating the need to account for the prevalence of infectious agents in drug approvals across regions and react.
External Factors - Nutritional Differences
Malnutrition remains a severe problem in resource-limited countries and is increasingly a significant problem in high-income countries. Our understanding of the mechanisms of drug-induced nutritional deficiencies has increased dramatically over the past decade.
Medications can exacerbate overt nutritional deficiencies, including vitamin B1 and B12, associated with alcohol and proton pump inhibitors, respectively, and calcium deficiency caused by anticancer drugs. Dietary composition (determined by socioeconomic status and cultural factors) may also be necessary.
Food composition can also affect intestinal transporters involved in drug absorption, and some fruit juices inhibit the intestinal absorption transporter OATP2B1 and may reduce drug absorption. Dietary supplements, herbal remedies, and concomitant medications may also affect drug absorption and disposition by inducing and inhibiting transporters and enzymes.
Components in St. John’s wort are known to induce drug-metabolizing enzymes, leading to crucial dietary supplement-drug interactions. Therefore, nutritional factors and concomitant medications should be considered when conducting clinical trials. In some cases, these factors can be investigated in a postmarketing setting without delaying access to essential medicines.
Internal Factors - Differences in Human Genetics
Like genetic diversity in pathogens, human genetic diversity is responsible for some interregional/intranational differences in disease risk, drug safety, and response. Genetic diversity in genes encoding proteins involved in drug absorption, distribution, metabolism, and elimination (ADME), such as cytochrome P450 enzymes (CYPs), conjugating enzymes, and transporters, leads to clinically relevant changes in drug exposure, including genome-wide Genetic studies, including association studies (GWAS), have identified many genes responsible for pharmacological variation that may vary by race.
CYP2D6, an enzyme responsible for metabolizing more than 25% of prescribed drugs, is a striking example of allele frequency variation in specific populations. This polymorphic enzyme has more than 100 alleles, the frequencies of which may vary among people. For example, the reduced-function allele CYP2D6*4 has an allele frequency as high as 18% in Europeans and less than 1% in East Asians. Although these individuals have a higher frequency of the CYP2D6*5 allele, this is another allele with reduced function.
ABCG2, the gene encoding breast cancer resistance protein (BCRP), also has a common loss-of-function genetic variant that limits drug absorption through intestinal efflux. Lower doses of rosuvastatin are generally recommended for East Asians because they have a higher variant allele frequency and, thus, higher bioavailability. As with drug interactions, studies of individuals carrying genetic polymorphisms can often be performed in a postmarketing setting, recognizing that genetic variation is not geographically isolated as the global population disperses.
How to Overcome Differences?
Scientific progress has brought many new devices, drugs, and treatments, improved human health concepts, medical technology, and disease treatment levels, saved the lives of many patients, and accelerated the discovery, development, evaluation, and approval of medical products. These advances advance our understanding of the intrinsic and extrinsic factors that govern drug disposition, toxicity, and response.
Although new technologies have improved our understanding of relevant differences affecting treatment response, many new technologies are unavailable in resource-limited countries, where they could have an enormous impact. For example, in vitro and computational analysis methods (plus operations) can predict drug safety, efficacy, and response in different ethnic groups.
Medicilon Preclinical Pharmacokinetics Department has professionals with rich theoretical knowledge and practical experience in experiment design, implementation, bioanalysis, and data analysis. Our Pharmacokinetics Lab has passed the GLP certification by NMPA. We are following the guiding principles of ICH, NMPA, and FDA. The lab offers in vivo and in vitro pharmacokinetic tests for our client’s needs and provides complete pharmacokinetic evaluation and optimization services. Our acclaimed quality data collection and efficient experiment can meet our clients’ needs from early drug discovery to new drug filing.
Medicilon's Preclinical Pharmacokinetics Services
References:
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[2] Patented Medicine Prices Review Board. Oncology Medicines in Canada: Trends and International Comparisons, 2010–2019. NDPUIS; Ottawa, ON, Canada: 2020.
[3] Jennifer L Wilson, Kit Wun Kathy Cheung, et al. Scientific Considerations for Global Drug Development. Sci Transl Med. Published in final edited form as: Sci Transl Med. 2020 Jul 29; 12(554): eaax2550. Doi: 10.1126/scitranslmed.aax2550.
[4] Aung Myint Thu, Aung Pyae Phyo, et al. Combating multidrug‐resistant Plasmodium falciparum malaria. FEBS J. 2017 Aug; 284(16): 2569–2578. Published online 2017 Jun 30. doi: 10.1111/febs.14127.
