Innovations in CRAMS How Indian Pharma Companies are Revolutionizing the Industry

Innovations in CRAMS: How Indian Pharma Companies are Revolutionizing the Industry

An era of COVID has indeed changed the whole scenario in the pharmaceutical industry. With the wide range of disruptions and challenges fought due to the coronavirus, various technologies like AI (Artificial Intelligence), quantum computing etc., have got acceptance by different pharmaceutical companies to help conduct R&D efforts, create personalized products and much more. 

In this, the Contract Research and Manufacturing Services or CRAMS, a rapidly growing industry has revolutionized the pharmaceutical industry. They provide cost-effective solutions to pharmaceutical companies, allowing them to focus on their core competencies. 

In all this, innovation is a must and is at the heart of the CRAMS industry. India is one of the leading players in the CRAMS industry, with its pharma companies at the forefront of innovation. Moreover, the global CRO (Contract Research Organisation) as per market value has mainly, reached $39 billion in 2018 and around $44 billion in 2021. 

In this article, we will explain the innovations in CRAMS and how Indian pharma companies are revolutionizing the industry.

What is CRAMS?

CRAMS stands for Contract Research and Manufacturing Services. It involves outsourcing drug development, manufacturing, and research services to third-party providers. It is a procedure where the product’s parent doesn’t produce the item themselves but gets it done by other organizations known as Contract Research Organisations (CRO). 

While understanding CRAMS, there are some important aspects including:

  • Cost-effective solutions
  • Quality assurance
  • Regulatory compliance
  • Intellectual property
  • Process improvement.

Cost-Effective Solutions:

One of the primary advantages of CRAMS is the cost-effective solutions it offers. By outsourcing drug development, manufacturing, and research services, pharmaceutical companies can focus on their core competencies and reduce costs. The involvement of CRAMS in research and manufacturing services offers cost-effective solutions to pharmaceutical companies, allowing them to develop and manufacture drugs and make them available at a lower cost.

Quality Assurance:

Quality assurance is critical in the CRAMS industry, and Indian pharma companies like Globela Pharma ensure that they meet regulatory requirements and maintain high-quality standards. Without proper quality assurance, the drugs manufactured by drug manufacturing companies may cause harm to the patient. 

The various pharma companies rely upon the contract service provider to accelerate research and manufacturing services. Indian pharma companies are investing in quality assurance processes, including quality control and quality assurance systems, to ensure that drugs meet regulatory requirements and are safe for patients.

Regulatory Compliance:

Regulatory compliance is another salient feature of the CRAMS industry. Indian pharma companies like Globela Pharma are ensuring that they comply with all regulatory requirements to be fulfilled. They are investing in regulatory compliance processes to ensure that drugs meet all regulatory requirements and are safe for patients. 

This process is necessary for the safety of individuals consuming drugs and other medicated products. Any inferior or ignorant quality procedure at any stage can compromise the health of the patients. Hence, it is vital to regulate proper regulatory compliance to keep the health of individuals uncompromised.

Intellectual Property:

Intellectual property is an asset that pertains to original and novel creations from the human brain or intellect. It may include copyrights, patents and regulatory licences. The Indian pharma companies are ensuring that they protect their intellectual property. Indian pharma companies are investing in intellectual property processes, including patent protection and trademark registration, to protect their innovations and ensure they are not infringed upon.

Process Improvement:

Improvement is something that any working era always has a space for. So is in the CRAMS industry as well. The Indian pharma companies are continuously improving their processes to increase availability, efficiency and reduce costs. 

They are investing in process improvement processes, including lean manufacturing, availability, and affordability of manufacturing services at a very minimal and justified amount.

Innovations in the field of CRAMs

One of the innovations in the CRAMS industry is the use of technology to improve drug development and manufacturing processes. Indian pharma companies are leveraging technology to develop new drugs, improve manufacturing processes, and ensure regulatory compliance. These all require constant efforts and various authentic technologies and collaboration with other companies to maintain quality assurance and the best results.

Technologies aiding in revolutionizing the industry:

One of the innovations in the CRAMS industry is the use of technology to improve drug development and manufacturing processes.

A few innovations that promote revolutionary change and progress in the industry are:

  • AI or Artificial Intelligence – AI is helping industries accelerate the discovery and manufacturing process of drugs. 
  • Huge data and analytics – The cost of production of medicines become the biggest hurdle in launching a new medicine. However, by using data and analytics, Indian Pharmaceutical companies can reduce the exploration cycles and make the new drug or vaccines available sooner for use. 
  • Bioprinting – One of the biggest challenges that are faced by Pharmaceutical companies is clinical trials. Bioprinting technology enables the exact imitation of human organs using the 3D technique. Pharmaceutical companies check the efficacy and effects of a drug on live subjects to observe all the vital changes. Hopefully, bioprinting now can save time as well as effort and also has reduced the dependency on live subjects to initiate clinical trials. 

Role of Collaboration to Uplift the Indian Pharma Companies

Another innovation in the CRAMS industry is collaboration. Indian pharma companies are collaborating with other companies and research organizations to promote drug development, cost-effective solutions, improve manufacturing processes, and share knowledge and expertise. 

This collaboration allows companies to pool resources and knowledge, leading to faster drug development and improved manufacturing processes. Moreover, the companies like globelapharma are working on great R&D efforts, quality manufacturing, and a sturdy distribution system with collaboration. 

Conclusion:

The Indian pharma companies are revolutionizing the CRAMS industry and paving the way for the development of new and innovative drugs. Through new technologies, collaboration, etc., pharmaceutical companies are getting the support they need to achieve growth, find flaws, initiate new conversions, and ultimately provide better health care. 

Moreover, India has already presented itself to be a cost-efficient and quality manufacturer for many Pharma companies. Therefore, with technological advancements and innovations continuing to progress, the pharmaceutical industry is expected to grow and evolve quickly. Thus, its demand will increase in the future throughout the world.

Solving healthcare challenges in underserved regions across the world

Solving healthcare challenges in underserved regions across the world

Introduction:

Healthcare is a primary necessity for every human being, whether you are living in a developed country, a developing country, or any underserved region. Globally, there are numerous healthcare challenges and in underserved regions, healthcare has always been in worse condition than in other parts of the world. 

Countries like Africa, the Middle East, South and South East Asia and Latin America with Africa being one of the most affected, witness more challenges to ensure proper health due to numerous reasons. These regions often lack the vital resources, infrastructure, and healthcare professionals to provide adequate medical care to their populations. 

However, healthcare innovation, research, and development can help address these challenges and improve healthcare outcomes in underserved regions. In this article, we will explore concerning innovative solutions that can help solve healthcare challenges in these underserved regions.

What are the challenges faced by underserved regions to reach out to healthcare? 

Countries like Africa, the Middle East, and South and South East Asia witness more challenges in the healthcare system.

The key disputes that come to underserved regions to achieve good health include are:

  • Low access to healthcare services
  • Shortage of good quality medicines at affordable prices
  • Lack of awareness
  • Unavailability of knowledge 
  • Limited access to various facilities

Solutions to improve healthcare challenges in underserved regions across the world

There are a lot of changes needed for a strong healthcare system. While, it can be achieved through investments in healthcare infrastructure, training of healthcare professionals, provision of medical equipment and supplies and many more. 

Some of the major solutions to strengthen the healthcare system in underserved regions are: 

  • Availability of Telemedicine
  • Educating people about health and its importance 
  • Making healthcare professionals and medicine easily accessible
  • Providing quality medicines
  • Boost medical research
  • Promote more pharmaceutical manufacturing

Availability of Telemedicine– It can enable people in underserved areas to have consultations with specialists even at a long distance. It can be particularly effective in rural areas where only a few healthcare facilities and specialist healthcare professionals are available. 

Educating individuals – Increasing education about healthcare can help improve access to healthcare. This empowers them to take control of their health and seek medical care when needed. Also, educating individuals about the importance of personal hygiene, sanitation, hand washing, and seeking medical help at the right time helps them to avoid any worse conditions. 

Making healthcare easily accessible – Accessibility is the key to a better healthcare system. In underserved regions building primary healthcare centres with high-quality pharmaceutical medicines, medical equipment, and facilities is critical to building a sound healthcare system. 

Providing quality medicines- When it comes to build-up a strong healthcare system the vital factors are availability, quality and affordability of medicines. In terms of quality of medicines, Globela Pharma is providing good value medicines through their continuous efforts and innovations. As part of the solution to the healthcare crisis in underserved regions, it is necessary to innovate affordable pharmaceutical solutions without compromising on quality. It is essential to reach out to every corner of the globe so that everyone has access to quality medicine regardless of their financial capacity. 

Boosting medical research- Medical research is essential to addressing healthcare challenges in underserved regions. It will help identify the most persistent healthcare challenges and develop solutions. One example of successful medical research is the development of vaccines and immunizations. Vaccines are critical in preventing the spread of infectious diseases such as HIV/AIDS, Malaria, Tuberculosis, Cholera, and Neglected tropical diseases. In addition, vaccines can help prevent seasonal infections and allergies.

Pharmaceutical manufacturing – It can help address healthcare challenges by ensuring that essential medicines are available to these people at a very affordable price. Where there is no comprise on the quality of the medicine, despite their financial status it will help in strengthening the healthcare system. Although, this can be achieved through partnerships between pharmaceutical companies and governments in underserved regions.

What innovative steps can be taken to resolve some common issues in underserved areas?

In underserved regions, some diseases are more prevalent than others like malnourishment, diabetes, infectious disease, etc. In order to combat these diseases definite innovative measures are necessary. Such as: 

  • Non-communicable diseases: A group of diseases like diabetes, cardiovascular disease and cancer are becoming increasingly prevalent in underserved regions. A multifaceted approach is needed to address these diseases, which includes healthcare innovation, strengthening of the healthcare system, and educational efforts in the healthcare field. 

For instance, promoting innovation in forming mobile health applications will help individuals monitor their health. This type of innovation will help address the problem as early as possible. Additionally, healthcare education is also critical in managing these diseases. It can include education on healthy lifestyles, such as healthy eating and exercise. 

In addition, making people aware of the importance of regular medical checkups will help reduce the complications associated with these diseases.

  • Neglected Tropical Diseases: A group of diseases that affect more than one billion people globally, relatively more in underserved regions. These diseases include dengue, chikungunya, Guinea-worm disease, leprosy, lymphatic filariasis, onchocerciasis, sleeping sickness, etc. The aim of solving the healthcare challenges in the underserved region requires scaling up through improving public health. 

For that, it is vital to establish a public health centre with adequate medical professionals, good quality pharmaceuticals, and medical equipment. Moreover, in managing NTDs, it is essential to regulate water sanitation and hygiene properly. 

  • Malnutrition and Poverty: Malnutrition and poverty are significant healthcare challenges in underserved regions. A wide approach can be addressed to improve the status of malnutrition and poverty in these underserved areas. 

Poverty reduction is also critical in addressing malnutrition and poverty. This can be achieved through investments in education, job creation, and social safety nets. 

In addition, increasing healthcare awareness and education can help individuals take control of their health and seek medical care when needed.

Conclusion:

In a nutshell, we all know that in various parts of the globe, people are not fortunate enough to access all the health facilities and take advantage of them. Hence, the healthcare challenges in underserved regions are complex and multifaceted. However, healthcare innovation, research, and development can help address these challenges and improve healthcare outcomes in these regions. 

By working together and leveraging technology, we can help ensure that everyone has access to the medical care they need to live healthy and productive lives. There is a very well-known saying that “HEALTH IS WEALTH”. By drawing a good amount of attention towards the healthcare sector we can not only save a good amount of wealth but can also provide a great amount of happiness in their life, to cherish it happily with family, friends and loved ones.

Cancer blog-min

The Importance of Early Detection and Prevention of Cancer

Introduction

Health is indeed the greatest wealth one can have.  Being vigilant towards the health of yourself and your loved ones is a top priority. This involves routine health check-ups and regular monitoring required as per physician’s advice relevant to an individual’s medical history. Any disturbance found in the body’s normal rhythm can hence be caught at an early stage and appropriate measures can be taken for its treatment and/or management. Amongst other ailments, cancer diagnosis can be most terrifying. Since there is no definite cure for Cancer, early stage diagnosis can greatly help in better treatment outcome and improved Quality of life.

Role of early diagnosis & screening-

The two main components of early detection of cancer are, i) early diagnosis and ii) screening. Early diagnosis focuses on detecting symptomatic patients as early as possible, while screening refers to the use of tests performed to detect cancer early on healthy individuals who have not yet shown symptoms of disease and are asymptomatic. The aim of screening is to reduce ailments and mortality caused by cancer. It is an effective method which is widely accepted and beneficial to people who are at risk with regards to cancer. This is crucial as it is one of the first actions taken to prevent disease. Furthermore, patients whose cancer is detected at an early stage possess a higher chance of cured disease, complete recovery, increased quality of life and longevity. Efforts to improve the selection of candidates for cancer screening, in order to understand the biological basis of carcinogenesis, and the development of new technologies for cancer screening will allow for improvements in the field over time.

Goals of early detection- 

The goal of cancer screening and early detection is to cure cancer by detecting the malignancy, or its precursor lesion, at an early stage prior to the onset of symptoms, when treatment of cancer is most effective. Indeed, overall cancer mortality has decreased by 25% from 1990 to 2015 for the United States U.S.), with even greater declines in the mortality rates for colorectal cancer (47% among men and 44% among women) and breast cancer (39% among women). A portion of this decrease can be attributed to the introduction of high-quality cancer screening for colorectal and breast cancer. The most successful cancer screening programs lead to the identification of precursor lesions (e.g., cervical intraepithelial neoplasia (CIN) with cervical cancer screening and colonic polyps with colorectal cancer screening) where the treatment of the precursor lesion leads to a decrease in the incidence of invasive and lethally spreading cancer over a period of time.

Application of various Imaging techniques-

Imaging tests used in diagnosing cancer may include Computed tomography (CT) scan, Magnetic resonance imaging (MRI) scan, Breast MRI, X-rays and other radiographic tests, Mammography, Nuclear medicine scans (bone scans, PET scans, Thyroid scans, MUGA scans, gallium scans), Ultrasound. Imaging tests are only part of cancer diagnosis and treatment. A complete cancer work-up includes assessment of medical history by a certified health care professional, a thorough physical exam, blood work and other lab tests.

Biopsy & its types-

Biopsy is another method that aids in detection of Cancer. It is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a disease. The most common types of biopsy includes: (1) Incisional biopsy, in which only a sample, part of affected tissue is removed; (2) Excisional biopsy, in which an entire lump or suspicious area is removed; and (3) Needle biopsy, in which a sample of tissue or fluid is removed through a needle aspiration. Depending on the type of needle used, the procedure is called a core biopsy when performed with a wide needle, and fine-needle aspiration biopsy when a thin needle is used.

Genetic & DNA testing-

Genetic testing is another effective method in Screening for Cancers. It helps in discovering certain mutations (changes) in genetic make-up of an individual, which are more prone to getting certain cancers. The most commonly mutated gene in people with cancer is p53 or TP53. More than 50% of cancers involve a missing or damaged p53 gene. Most p53 gene mutations are acquired. Germ line p53 mutations are rare, but patients who carry them are at a higher risk of developing many different types of cancer.

Routine examinations required to check for warning signs that may lead to Cancer-

There are few warning signs and symptoms that should not be neglected for better health. They are as follows:

-A sore that does not heal, delayed or slow healing

-Unusual bleeding or discharge.

-Thickening or lump in breast or elsewhere.

-Indigestion or difficulty in swallowing.

-Obvious change in wart or mole.

-Nagging cough or hoarseness.

 -A change in bowel habits, including diarrhoea, constipation or consistency of your stool.

-Persistent abdominal discomfort such as cramps, gas or pain.

-Rectal bleeding or blood in your stool.

-Unexplained weight loss.

-Weakness or fatigue, which does not get better after adequate rest.

Importance of early diagnosis and its comparison with late stage diagnosis; along with their respective prognosis-

Lack of early screening leads to late stage diagnosis. In most cases, patients who are diagnosed with cancer at earlier stages show improved survival, clinical outcomes and better quality of life. However, screening for earlier cancer detection remains limited. As of year 2021, broad-based cancer screenings for asymptomatic patients are recommended in the US for just 5 cancer types (breast, cervical, colorectal, lung for a high-risk subset of the population, and prostate).Statistically, 71% of all cancer mortality is from cancers that lack broad-based screenings for asymptomatic patients. Thus, earlier cancer diagnosis results in improved survival. Patients diagnosed with earlier stages of cancer (stage I-II) generally have a higher likelihood of recovery than those diagnosed at a later stage (stage III-IV). For non-small cell lung cancer (NSCLC), stomach, and pancreatic cancers, between 36% and 53% of patients are diagnosed with stage IV cancer, where the cancer has spread to other parts of the body, decreasing survival chances. The 5-year survival rate for non-small-cell lung cancer (NSCLC), stomach, and pancreatic cancers, doubles in all cases when detected at earlier stages. These differences in survival rates emphasize the opportunity to make progress in beating cancer by decreasing late-stage diagnoses with improved and expanded screenings.

Suffering patients progress through more extensive treatment demanded by later stage diagnosis. Quality of life goes down including through physical, emotional, and social functioning. Late-stage diagnosis often requires more intensive and more invasive interventions that result in sometimes difficult and lasting side effects. For example, patients with late-stage NSCLC diagnosis often suffer from dyspnoea, or laboured breathing, after their treatment is complete. Similarly, stomach cancer patients recovering from a partial or full gastrectomy followed by other treatments such as chemotherapy, radiation, and immunotherapy in late stages may suffer from chronic fatigue, difficulty eating, and challenges performing everyday activities.

Conclusion-

A plan for early diagnosis is a key component in controlling and preventing cancer. Main goal is to cure cancer patients, prolong their life considerably while ensuring a good quality of life. Treatment plans need to be integrated with a palliative care programme, so that patients with advanced cancers, who can no longer benefit from treatment, will get adequate relief from their physical, psychosocial and spiritual suffering. Additionally, programmes should include an awareness-raising component, to encourage and educate patients, family and community members about the cancer risk factors and the need for taking preventive measures to avoid contracting cancer.

R&D blog-min

Role of Research and Development in Modern Pharmaceutical Industry

Introduction

In a life cycle of a drug from its discovery till launch, a series of crucial steps are involved in order to comply with regulatory requirements as per respective local regulatory authority. These steps from discovering a new drug to its launch in the market contributes to research and development in the pharmaceutical industry. The process is time consuming and may take several years for completion.

Steps involved in research and development in the modern pharmaceutical industry are as follows, i) early drug discovery, ii) preclinical studies, iii)clinical development, iv) review and approval by applicable regulatory bodies, v) post marketing surveillance.

Identifying a potential target-

Early drug discovery involves target identification and validation, hit discovery, assay development and screening, high throughput screening, hit to lead and lead optimization. Target identification begins with identifying the function of potential therapeutic agents and its role in the disease. It can be approached by direct biochemical methods, genetic interactions or computational interface. However, a combined approach may be required to fully characterize on-target and off-target interactions in order to understand molecular action mechanisms. Main motive of hit discovery is to identify molecules with potential interactions with drug targets.

Assay development-

Different types of assays can be used for assay development and compound screening, ranging from biochemical to cell-based assays. The choice of the assay depends on the biology of the drug target protein, scale of the compound screen, the equipment infrastructure, etc. Factors required for assay development are; i) Pharmacological importance of the assay– ability to identify compounds with the desired mechanism of action, ii) Reproducibility– is readily reproducible across assay plates, screen days and the length of the drug discovery programme, iii) Quality– pharmacology of the standard compounds falls within predefined limits, iv) Effects of compounds in the assay– should not be sensitive to the concentrations of solvents used in the assay.

Screening methods-

High throughput screening, (HTS) involves screening of the entire compound library against the drug target. Knowledge-based screening is a method of selecting from the chemical library smaller subsets of molecules with potential activity at the target protein. Fragment screening is making very small molecular weight compound libraries which are screened at high concentrations. Physiological screening is a tissue-based approach with the response more in direction with the desired in vivo effect.

Lead optimization-

Drug-like molecules must go through different phases to identify the hit lead molecule and optimization with a potency of 100nM – 5mM at the drug target. The refinement process involves generating dose-response curves in primary assay for each hit. Followed by examining the surviving hits in a secondary assay. Generation of rudimentary structure-activity relationship, SAR data and identifying the essential elements in the structure linked with the activity. Lastly, in vitro assays providing significant data with regards to absorption, distribution, metabolism and excretion (ADME) properties as well as physicochemical and pharmacokinetic (PK) measurements. Overall, the aim is to achieve a lead compound optimized with desirable effects on the target that can provide therapeutic benefits within an acceptable safety window. Average time required for this step is 2-6 months.

A glance at preclinical trials-

Preclinical studies or non clinical studies, carries out testing on animals to accurately model the desired biological effect of a drug in order to predict treatment outcomes in patients determining its efficacy, and to identify all toxicities associated with the drug to predict adverse effects for safety assessment. There are two types of preclinical studies, i) in vitro, ii) in vivo, iii) ex vivo assay and iv) in silico. In compliance with good laboratory practices, GLP, in vitro studies are carried out outside of living organisms in a test tube, glass or petri dish. On the other hand, in vivo studies are those which involve living organisms, including animal studies and human clinical trials. Ex vivo assay refers to a medical procedure in which an organ, cell or tissue are taken from the living body for treatment testing such as skin biopsies or isolated samples from tumor biopsy. In silico studies refers to using computer simulations to predict the reaction of a compound with specific proteins or pathogens. 

Goal of preclinical studies involve determination of pharmacokinetics, proof of concept, formulation, optimization & bioavailability, establishing safe dose, therapeutic dose, lethal dose and maximum tolerated dose. The compound from drug discovery is modified through preclinical studies and becomes Investigational New Drug, IND. IND application is filed for review and approval as per guidelines and standards of local and national regulatory authority. On an average the time required for this phase is approximately ranging from 1-6 years.

A complete overview of Clinical trials-

Clinical development of drug discovery begins after approval of IND for further testing. Clinical trials are conducted for testing of the new drug classified into several phases.

Phase 0 and Phase I-  Phase 0 is known as human micro dosing studies, which involves 10-15 individuals who are administered with small amounts of sub therapeutic dose mainly to determine pharmacokinetics, oral bioavailability and half-life of the drug. Phase 0 trials are often skipped to direct Phase I trials unless some of the data is inconsistent from previously conducted preclinical studies. Phase I studies are conducted amongst healthy volunteers to test the safety, tolerability, pharmacokinetics & pharmacodynamics, side effects & adverse effects, optimum dose, half-life and formulation method for the drug. In circumstances when testing for diseases like cancer or HIV, the treatment for which is likely to make healthy individuals ill, clinical patients are selected as an exception. Phase I trials are not randomized and hence are vulnerable to selection bias. This phase involves 20-100 individuals. Phase I trials can be further divided into, i) Single ascending dose, Phase I (a) in which a small number of participants are entered sequentially at a particular dose while monitoring them for a period of time to confirm safety. If no adverse effects are noted, then dose is escalated for newer groups. It is continued until pre-calculated pharmacokinetic safety levels are achieved or intolerable side effects are noted, it is the point where drug reaches at maximum tolerated dose, MTD; ii) Multiple ascending dose, Phase I (b) in which group of participants receives multiple low doses of the drug, which is subsequently escalated for further group of participants up to a predetermined level. It helps in determining pharmacokinetics and pharmacodynamics of multiple doses of the drug along with its safety and tolerability.

Phase II- Phase II trials are performed on larger groups (50–300) and are designed to assess biological activity and effect of the drug. Trial design of Phase II trials are either as case series, which demonstrates safety and efficacy in a selected group of participants, or as randomized controlled trials ,RCT, where some participants receive the drug/device and others receive placebo/standard treatment. Phase II studies are divided into Phase II (a) and Phase II (b). Phase II (a) studies are pilot studies designed to demonstrate clinical efficacy or biological activity of the drug. Phase II (b) studies determine the optimal dose at which the drug shows biological activity with minimal side-effects. It is also known as maximum effective dose, MaxED.

Phase III- Phase III trials are conducted in a large patient population of 300-3000 individuals determining the efficacy of the new drug in comparison to existing standard treatment. They are time consuming and expensive with complicated trial designs such as Randomized controlled multicentre trials with single, double or triple blinded factors in order to avoid bias and clean results. Phase III (a) studies are trial designed and executed to obtain statistically significant data for new drug approval by regulatory authority. Phase III trials that continue while awaiting regulatory approval in order to provide life-saving drugs to patients until the drugs are available in the market are categorized as Phase III (b) studies. Label expansion studies by the sponsor also fall under this category.

Phase IV- If the new drug successfully passes through Phase I, II, and III, with desirable outcomes, the manufacturing, preclinical and clinical data is then submitted as a new drug application, NDA, for review and marketing approval by national applicable regulatory authority. Post approval the new drug is marketed and Phase IV trials begin, which is post marketing surveillance of the new drug and lasts for up to 5 years. The entire process from developing a drug from preclinical research till marketing can take approximately 12-18 years. A Phase IV trial is a drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test. These trials involve the safety surveillance, i.e, pharmacovigilance and ongoing technical support of a drug after it receives regulatory approval to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive reasons, such as finding a new market for the drug, or other reasons, for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials. The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being withdrawn from the market or restricted to certain uses; examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).

Conclusion

Thus Research & Development is essential when it comes to the pharmaceutical industry, since R&D services not only generate income for the companies involved in the research but it often saves lives. Reliable Pharmaceutical R&D services allow for companies to have technical and manufacturing procedures, quality control measures and production scope aspects as per required standards.

Drug Discovery Blog-min

How we test safety and efficacy of new drugs.

Introduction

The concepts of efficacy and safety have been with mankind since ages. In native sense, an efficacious and safe medical intervention is one that works and causes no undue harm. A drug should be used only when it will benefit a patient. Benefit takes into account both the drug’s ability to produce the desired result (efficacy) and the likelihood of adverse effects (safety). For a major portion of the history of medicine, efficacy and safety were measured by that native standard, which till today lies at the heart of medical practice, but the meaning and measurement of those concepts have evolved with increased sophistication and advancement of scientific methods in medicine. This article introduces the concepts of efficacy, effectiveness and adverse effects. It also throws light on patient oriented and surrogate outcomes along with their comparison and correlation in safety assessment of new drugs. Lastly concluding with the importance of long term monitoring and assessment of benefit to risk ratio for new drugs.

How does efficacy & effectiveness differ from eachother?

Efficacy is the capacity to produce an effect (e.g., lower blood pressure, lower or control high blood sugar). Efficacy can be assessed accurately only in ideal conditions (i.e., when patients are selected by proper criteria and strictly adhere to the dosing schedule). Thus, efficacy is measured under expert supervision in a group of patients most likely to have a response to a drug, such as in a controlled clinical trial.

Effectiveness differs from efficacy because the former takes into account the overall performance of the drug to real world use. Often, a drug that is efficacious in clinical trials is not very effective in actual use. For example, a drug may have high efficacy in lowering blood pressure but may have low effectiveness because it causes undesirable adverse effects which makes it difficult for patients to adhere to it. Effectiveness also may be lower than efficacy if clinicians inadvertently prescribe the drug inappropriately (e.g., giving a fibrinolytic drug to a patient thought to have an ischemic stroke, but who had an unrecognized cerebral haemorrhage on CT scan). Thus, effectiveness tends to be lower than efficacy.

Patient-oriented outcomes & Surrogate outcomes-

Patient-oriented outcomes should be used rather than surrogate or intermediate outcomes to judge efficacy and effectiveness. Patient-oriented outcomes are those that affect a patient’s well-being. They involve prolongation and better quality of life, improve function or prevent disability, and provide relief from symptoms. Surrogate or intermediate outcomes are factors that do not directly involve the patient’s well-being. They are features such as physiologic parameters (e.g., blood pressure) or test results (e.g., concentrations of glucose or cholesterol, tumour size on CT scan) that are thought to predict actual patient-oriented outcomes. For example, clinicians typically presume that lowering blood pressure will prevent the patient-oriented outcome of uncontrolled hypertension (e.g., death resulting from myocardial infarction or stroke). However, it is conceivable that a drug could lower blood pressure but not decrease mortality, perhaps because it has fatal adverse effects. Also, if the surrogate is merely a marker of disease (e.g., HbA1C) rather than a cause of disease (e.g., elevated blood pressure), an intervention might lower the marker by means that do not affect the underlying disorder. Thus, surrogate outcomes are less desirable measures of efficacy than patient-oriented outcomes.

On the contrary, surrogate outcomes are more feasible to use, for example, when patient-oriented outcomes take a long time to appear (e.g., kidney failure resulting from uncontrolled hypertension) or are rare. In such cases, clinical trials would need to run for a long time unless a surrogate outcome (e.g., lowered blood pressure) is used. In addition, the main patient-oriented outcomes, death and disability, are binary (i.e., yes/no), whereas surrogate outcomes are often continuous, numerical variables (e.g., blood pressure, blood glucose). Numerical variables, unlike binary outcomes, may indicate the magnitude of an effect. Thus, use of surrogate outcomes can often provide much more data for analysis than can patient-oriented outcomes, allowing clinical trials to be done using limited patients for a certain amount of time.

Correlation of patient-oriented and surrogate outcomes- 

However, surrogate outcomes should ideally be proved to correlate with patient-oriented outcomes. There are many studies in which such correlation appeared reasonable but was not actually present. For example, lowering blood glucose to near-normal concentrations in patients with diabetes in the intensive care unit resulted in higher mortality and morbidity (possibly by triggering episodes of hypoglycaemia) than lowering blood glucose to a slightly higher level. Some oral antihyperglycemic drugs lower blood glucose, including HbA1C concentrations, but do not decrease risk of cardiac events. Some antihypertensive drugs decrease blood pressure but do not decrease risk of stroke.

Factors that help in assessing safety index of drugs-

Adverse Effects are clinically relevant undesirable effects that are patient-oriented outcomes, such as, death, disability or discomfort. Surrogate adverse effects (e.g., alteration of concentrations of serum markers) are often used but, as with surrogate efficacy outcomes, should ideally correlate with patient-oriented adverse effects. Clinical trials that are carefully designed to prove efficacy, can still have difficulty identifying adverse effects, if the time needed to develop an adverse effect is longer than the time needed for benefit to occur or if the adverse effect is rare. For example, cyclooxygenase-2, COX-2 inhibitors relieve pain quickly, and thus their efficacy can be shown in a comparatively brief study. However, the increased incidence of myocardial infarction caused by some COX-2 inhibitors, such as Rofecoxib marketed as Vioxx, occurred over a longer period of time that was not apparent in shorter, smaller trials. Hence, clinical trials may exclude certain subgroups and high-risk patients, adverse effects may not be fully known until a drug has been in widespread clinical use for several years. Post marketing surveillance or pharmacovigilance is one way to test for safety of new drugs in long term.

Another factor that ensures safety and efficacy of new drugs is benefit to risk ratio. Known or expected benefits vs. unknown or unexpected risks is when the efficacy of a new drug is tested, a specific type of benefit is expected. Other benefits are usually additional to the outcome sought. While assessing risk, the negative outcomes are often unknown or unexpected, and, unlike the additional benefits, the significance of these adverse effects must be considered to the extent practicable before the drug is considered for acceptable risk. When thalidomide was tested as a sleeping pill, no major negative effects were discovered. Its effects upon the fetus were not tested, and thalidomide was marketed as a safe drug. The birth defects that resulted, vividly demonstrates the need to consider risks from many perspectives. 

Conclusion-

The drug safety concept has earned a lot of attention during the last century due to the fact it plays a direct role in a patient’s health. Recent regulatory laws, stresses that drug safety should be included in the process of new medication’s approval and continued conduct of post-marketing drug evaluations, i.e., pharmacovigilance. Benefit–risk assessment should be considered by all health care professionals when they prescribe specific drugs to specific groups of patients. Hence, drugs with a high risk profile should be avoided unless their benefit outweighs the risk. Drug safety has gone through different stages from the last century till now, with several unfortunate tragedies that incline us to protect our patients from all aspects. All patients should be protected; however, specific groups of patients demand paramount care, such as pregnant women, children, and the elderly, since they are identified as vulnerable populations. 

Test-min

The science behind developing a new medicine

Introduction

The need for new medicine arises with time as older available medicines lose desirable effect due to tolerance or origination of newer diseases that require advance cure through new medicines. In order to treat a particular disease, it is important to understand the cause behind it. Attributes of disease such as acquiring, transmission and progression needs to be studied. Type of cells that are affected, alteration in genetic factors of diseased cells and the presence or absence of proteins in the affected cells should also be taken into account. In the case of infectious diseases, the characteristics of microorganisms and its replication in the human body requires thorough knowledge and understanding.

In modern day laboratory set ups, sophisticated tools are used for shedding light on above concerns. The tools are designed to discover the molecular roots of disease and pinpoint critical differences between healthy cells and diseased cells. By determining the molecular defects behind a particular disease, scientists can identify the best targets for new medicines. In some cases, the best target for the disease may already be addressed by an existing medicine, and the aim would be to develop a new drug that offers other advantages. Although, drug discovery aims to provide an entirely new type of therapy by pursuing a novel target.

Gathering data on disease progression-

Amongst different models of studying a disease, cell cultures help studying diseased and healthy cells and differences in cellular processes and protein expression. Cross species studies are done in which genes and proteins that are found commonly between humans and other species. Function of these human genes are revealed to be parallel with other organisms. Bioinformatics is a field of biotechnology that is associated with biology and information technology.  It aids in better assessment of disease. Biomarkers are protein substances used for measuring biological function, identifying disease processes or determining response to a therapy. They also have diagnostic applications. Proteomics is the study of protein activity within a given cell, tissue or organism. A change in protein activity can provide information on the disease process and the impact of medicines under study.

Drug discovery

  After crucial analysis of the disease in question, a target is selected or identified, which is supposed to have an effect by a novel intervention. For instance, cholesterol lowering drugs target enzymes that are involved in production of cholesterol. Antibiotics are designed to target specific proteins that are critical for survival of bacteria. Scientists and researchers estimate there are about 8,000 potential therapeutic targets that might provide a basis for developing new medicines. Most of them are proteins of various types, including enzymes, growth factors, cell receptors, and cell-signalling molecules. Some targets are present in excess during disease, so the goal is to block their activity which is achieved by developing a medicine that binds to the target and prevents it from interacting with other molecules in the body. On the other hand, the target protein is deficient or missing, and the goal is to enhance or replace it in order to restore healthy function. Advancements in the field of biotechnology have made it promising, to create therapies that are similar or identical to the complex molecules the body depends on to remain healthy. It is essential for researchers to prove the validity of a particular target through establishing its role in disease progression. The key is to demonstrate that the activity of the target is running the course of the disease.

Drug development

Once the target has been selected, the next step is to identify a drug that impacts the target in the desired way. Multiple chemical compounds can be studied simultaneously with a technology called drug screening. With automated systems, scientists can rapidly test thousands of compounds to observe the ones that interfere with the target’s activity. Potential compounds can be put through added tests to find a lead compound with the best potential to become a drug.

Collecting preclinical data

 Once a promising test drug has been identified, it must go through extensive testing before it can be studied in humans. This testing for analysing safety of a drug constitutes preclinical studies. Many drug safety studies are performed using cell lines engineered to express the genes that are often responsible for side effects. Cell line models have decreased the number of animals needed for testing and have helped accelerate the drug development process. Some animal tests are still required to ensure that the drug doesn’t interfere with the complex biological functions that are found in humans.

Clinical phases of drug testing

If a test drug has no serious safety issues in preclinical studies, researchers can seek permission from regulatory authority to perform clinical trials in humans. There are three phases of clinical studies which are executed in the form of clinical trials, and the new drug is required to meet certain criteria before moving on to the next phase.

Phase 1: Tests in 20 to 100 healthy volunteers and under special circumstances, patients. The main goals are to assess safety and tolerability and explore the behaviour of the drug in the body. Half-life of the drug is estimated.

Phase 2: Studies in about 100 to 300 patients. The goals are to evaluate the efficacy of the drug, calculate dosage based on data from preclinical studies and to explore the safety index of the drug.

Phase 3: Large studies involving 500 to 5,000 or more patients, depending on the disease and the study design. Large scale trials are often needed to determine if a drug can prevent negative outcomes on a patient’s health. The goal is to compare the effectiveness, safety, and tolerability of the test drug with standard drug or a placebo.

If the test drug shows clear benefits and acceptable risks in phase 3, the company can file an application requesting regulatory approval to market the drug. In India, the Central Drugs Standard Control Organisation, CDSCO, is governed by the Directorate General of Health Services, Ministry of Health & Family Welfare, MoHFW. Regulators review data from all studies conducted and make a decision whether the benefits of the medicine outweighs the risks it may have. 

New drug launch in the market

Post approval for marketing of the new drug, routine monitoring is required up till 5 years which is called Pharmacovigilance or Post marketing surveillance. It is Phase 4 of clinical studies. A pharmaceutical company can also continue its clinical trials on an approved drug to spot its effects under other specific conditions (alternative use) or in other groups of patients, and additional trials may also be required by regulatory agencies.

Conclusion

The whole drug development process from drug discovery till marketing approval takes 10 to 18 years to complete on average with high expenses going up to 1.3 billion USD. Only a limited number of drugs are able to achieve success through each phase. Hence, developing a new drug is an extensive process and the time, money and effort that goes behind it stands high for superior quality drugs becoming available in the market.