Drug Development

Drug

Drug development involve multiple stages. The process from start to finish can take lots of funding and time (many years). Large drug companies usually have multiple drug candidates that go through the development process at the same time. Out of the many, only a few will make it to regulatory approval and be sold to the public. This is the reason why new drug costs so much. The cost is to support this lengthy and costly process of drug development.

The process of drug development includes:

• Drug Discovery
• Pre-clinical testing
• Clinical trials
• Post market surveillance

Drug Discovery

Drug discovery is the process that new drug candidates are screened and selected. Thousands of potential small molecules, natural products, or extract are initially screened for desired therapeutic effects. For example, candidates for protease inhibitor should bind the protein protease with certain affinity, selectivity, potency, and metabolic stability. Oral stability and bioavailability should also be considered for the candidates to be made into a pill that can be swallowed. Once one or more top candidates are selected, the next step is to conduct pre-clinical testing to confirm safety, toxicity, pharmacokinetics and metabolism.

Pre-Clinical Testing

Prior to testing new drug candidate on human, extensive pre-clinical testing in animals must be done to ensure the safety of the new drug. Pre-clinical testing is also conducted to learn of any toxicity, metabolism profile, and pharmacokinetic of the new drug. Pharmacokinetic studies, commonly referred as PK studies, are conducted to learn what happens to the new drug in a living organism, from the moment it enters the body to the moment it get eliminated through urine and stool.  Pre-clinical testing also includes studying the biochemical and physiological effects of the drug on the body.  This is called Pharmacodynamics or PD studies.  PD studies aim to learn the mechanisms of drug action and the impact of drug concentration on the living organism.  From PK and PD studies, appropriate doses and dosing schemes of the new drug can be determined.

The chemical makeup of the new drug is also studied in pre-clinical testing. This includes the solubility, stability, and formulation of the new drug in different forms (capsules, tablets, aerosol, injectable, and intravenous). This portion of chemical studies is known as Chemistry, Manufacturing and Control (CMC).

In addition, other studies may include genotoxicity, carcinogenicity, and reproduction toxicity.

Clinical Trials

Once extensive pre-clinical testing showed promising results for the new drug candidate, the next step is to conduct clinical trial in human. In United States, prior to conducting clinical trial in human, an application to the FDA called Investigational New Drug (IND) application. Below is a link for FDA 21 CFR 312, the regulation that govern new drug candidate that requires IND.http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312

If the sponsor or drug manufacturer does not receive any objection notice from the FDA within 30 days after IND application submission and the clinical trial has been approved by the IRB, the clinical trial can start.

Clinical trials in human are often done in phases:

Phase 0 – Pharmacokinetics (PK) and Pharmacodynamics (PD)

This is first in human trial where pharmacokinetics (PK) and pharmacodynamics (PD) are studies. The number of subjects are usually very small (N = 10 to 15)

–        Pharmacokinetics (PK) studies are done similar to the PK studies described in pre-clinical testing to understand what happens to the new drug from the moment it under human body to excretion. PK studies are done to learn what the body does to the new drug.

–        Pharmacodynamics (PD) studies are opposite to the PK studies. PD studies are done to learn what the new drug does to the body.

NOTE: Phase 0 is commonly described as part of Phase I below.

Phase I – Safety

Phase I studies are often done in small number (N = 20 – 80) of healthy subject. The goal of this phase is to learn of the safety of the new drug. To avoid further complication and symptoms from underlining disease, healthy subjects are recruited into this phase. Exception to this includes oncology trials where actual disease patient may be used. Phase I studies are often done in a specialized facility or clinic where continuous monitoring of subjects can be done. These facilities or clinics are often called CPUs (Central Pharmacological Units). Side effects of the new drug are carefully recorded in phase I studies. In addition, phase I studies are often designed to test single (Single Ascending Dose) and multiple (Multiple Ascending Dose) dosage and dosing interval to learn of the range where the new drug is safe in human.

Phase II – Efficacy (Proof of Concept)

Phase II studies are done in larger number of subjects (N = 100 – 200). The population for this phase is patient with the disease where the new drug is intended to treat. Study design for phase II studies usually compares the new drug against standard care treatment and / or placebo group. Placebo is an inert substance that has no medical effect (e.g. sugar pill). The goal of phase II studies is to test for efficacy of the new drug. Additional safety information is also usually collected. Phase II studies can be done in two stages, phase IIa to compared dosing and dose regiment and phase IIb to evaluate efficacy and safety. Sometimes, phase I and phase II are done in combination to evaluate efficacy and toxicity in order to save time and cost. Since phase II studies evaluate efficacy, this phase can be referred as “Proof of Concept.” Phase II usually determine the fate of the new drug; continue to phase III if shown efficacy vs. discontinue clinical testing if shown ineffective.

Phase III – Pivotal Studies

Phase III studies are designed to obtain large enough population to show statistical evidence of efficacy and safety of the new drug. Phase III studies are often done in large number of patients with the disease the new drug is intended to treat (N = 300 – 3000). Similar to phase II, new drug in phase III studies are being compared against standard care treatment and / or placebo group. Due to the large number of patients being evaluated, phase III studies are time consuming and costly. Similar to phase II, phase III studies can be done in stages; phase IIIa to evaluate efficacy and safety and phase IIIb to evaluate additional disease indication or additional marketing claims. Due to the evaluation of efficacy and safety in large population, phase IIIa are often called “Pivotal Study.” While not required in all cases, often 2 successful phase IIIa trials are needed to show efficacy and safety to obtain regulatory approval from major regulatory bodies such as the FDA in the U.S. and EMA in European Union. Upon favorable results from these phase IIIa trials, sponsor or drug manufacturer may submit a New Drug Application (NDA) to the FDA or EMA for regulatory approval.

Phase IV – Post Marketing Surveillance

Phase IV studies are usually done after regulatory approval of the new drug. The goal of phase IV studies is to collect safety information in larger population (general population) and in longer time period (multiple years) than in phase I, II, and III trials. Phase IV studies are necessary to protect patient’s safety after regulatory approval of new drug. As safety information are collected and reported to the overseeing regulatory body, if serious side effects are found, the new drug may be restricted to certain use or it may be prohibited from being sold altogether.

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4 Important Healthy Diet Tips for a Fiber Fine Living

Consuming a healthy, healthy diet is an integral part of keeping great health, and can help you feel your best. It doesn’t have to be difficult either. Just follow these four tips to get started and our Canadian researcher form over here are for providing the 4 tips of healthy living.

Eat lots of clean fruit and veg

It’s suggested that we eat at least five parts of different types of fresh fruit and fresh vegetables a day. It’s easier than it appears to be. A glass of unsweetened 100% fruit juice (150ml) can count as one part, and fresh vegetables prepared into recipes also add to the count. Why not cut a banana over your morning hours meal, or exchange your regular mid-morning snack food for a piece of fruit?

Eat more fish

Fish is an excellent source of proteins and contains many nutritional supplements. Aim to eat at least two full fish a week, such as at least one part of oily seafood. It contains omega-3 body fat, which may help to prevent cardiovascular illness. You can select from fresh, freezing and canned: but remember that processed and smoked seafood can be great in sodium.Oily seafood consists of salmon, mackerel, trout, herring, fresh tuna, sardines and pilchards. Non-oily seafood consists of haddock, plaice, coley, cod, tinned seafood, skateboarding and hake. If you regularly eat a lot of seafood, try to select as wide a variety as possible.

Eat less salt

Even if you don’t add salt to your meals, you may still be overeating. About three-quarters of the salt we eat are already in the meals we buy, such as cereals products, cereals, bread and cereals. Consuming too much of it can increase your hypertension. People with hypertension are more likely to create cardiovascular illness or have a heart stroke.

Don’t get thirsty

We need to drink about 1.6 to 2 ltrs of water every day to stop us getting dried. This is in addition to the liquid we get from the meals we eat. All non-alcoholic beverages add to your healthy being, but water and lower-fat dairy are more healthy choices. Thus our Candian researcher form wishes you a healthy living by following the forgoing mentioned diet.

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Most Obese People Will Never Reach Normal Weight: Study

Weight loss is considered a major health goal for people who are obese, but the reality is that few reach a normal weight or keep any lost pounds off, a new study shows.

In any given year, obese men had a 1-in-210 chance of dropping to a normal weight, according to the study, which tracked over 176,000 obese British adults.Women fared a bit better: Their odds were 1 in 124, the study found.On the brighter side, people were far more likely to shed 5 percent of their body weight — which is considered enough to bring health benefits like lower blood pressure and blood sugar.Unfortunately, more than three-quarters gained the weight back within five years, the researchers reported online July 16 in theAmerican Journal of Public Health.

It all paints a bleak picture, the study authors acknowledged. And the findings underscore the importance of preventing obesity in the first place, said lead researcher Alison Fildes, a research psychologist at University College London.However, the study does not suggest that weight-loss efforts are futile, stressed Dr. Caroline Apovian, a spokeswoman for the Obesity Society who was not involved in the research.

“We already realize that it’s almost impossible for an obese person to attain a normal body weight,” said Apovian, who directs the Nutrition and Weight Management Center at Boston Medical Center.

She said the “stark” numbers in this study give a clearer idea of just how difficult it is.However, she added, the study was based on medical records, and there is no information on how people tried to lose weight. They might have tried a formal weight-loss program, or they might have tried a fad diet.”So this has no relevance to how effective weight-loss programs are,” Apovian said.Fildes agreed. On the other hand, she said, the results do reflect the real-world experience of obese people who are trying to shed weight.

“What our findings suggest is that current strategies used to tackle obesity are not helping the majority of obese patients to lose weight and maintain that weight loss,” Fildes said. “This might be because people are unable to access weight-loss interventions or because the interventions being offered are ineffective — or both.”For the study, Fildes and her team used electronic medical records to track weight changes among more than 176,000 obese adults between 2004 and 2014. The researchers excluded people who underwent weight-loss surgery, which is an option for severely obese people.

Overall, obese men and women had a low annual probability of achieving a normal weight — especially if they were severely obese. The odds were as high as 1 in 1,290 for morbidly obese men.People did stand a much better chance of losing 5 percent of their body weight: The yearly odds were 1 in 12 for men and 1 in 10 for women.The success, however, was usually short-lived: 78 percent gained that weight back within five years.

Apovian said that because dramatic weight loss is so difficult, obesity specialists do generally advise patients to set a goal of losing 5 percent to 10 percent of their starting weight.But as the current findings show, even that can be tough to maintain, she added.Part of the problem, according to Apovian, is that few obese Americans who are eligible for weight-loss medications or surgery actually do get those therapies.In the United Kingdom, the study authors said, people trying to tackle obesity usually get a referral from their doctor to a weight-management program, which would typically focus on calorie-cutting and exercise.

The new findings suggest that’s insufficient, according to Fildes and her team.For people who are already substantially overweight, Fildes said, staving off further weight gain is vital.”We would recommend obesity treatment programs prioritize preventing further weight gain and maintaining weight loss when it is achieved,” she said.But given the battle most obese people face, Fildes said, public health efforts to prevent obesity will be even more important.

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First Clinical Research Stock Index (FCRI)

Market Activity

FCRI gained 7% last month, while pharmas gained 3%, biotechs gained 3%, and the   general market gained 2%. Seven FCRI stocks gained and two declined. There were two   significant gainers: INC Research Holdings (+25%) and ICON (+20%). There were no   significant decliners.

Notes on Indices    First Clinical Research Index (FCRI). Calculated as the mean average percentage   change from baseline, dividends excluded, adjusted for stock splits. In other words, the   indices are not weighted for stock price or market capitalization. Prices are in local   currencies. Index components may change from time to time based on new listings,   mergers and other factors. Components include eight publicly traded clinical research   stocks: CMIC (2309:JP), EPS Co., Ltd. (4282:JP), Hangzhou Tigermed Consulting Co Ltd   (300347:CH), ICON (ICLR:US), INC Research Holdings (INCR:US), Medidata   (MDSO:US), PAREXEL International (PRXL:US), PRA Health Sciences (PRAH:US), and   Quintiles Transnational Holdings (Q).    S&P 500 Index (SPX). Capitalization-weighted representative sample of 500 mostly   large-capitalization companies in leading industries of the U.S. economy.    S&P 500 Pharmaceutical Index (S5PHARX). Capitalization-weighted S&P 500   companies engaged in research, development or production of pharmaceuticals.    S&P 500 Biotechnology Index (S5BIOTX). Capitalization-weighted S&P 500   companies primarily involved in development, manufacturing or marketing of products   based on advanced biotechnology research.

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Why an HIV Vax Only Works for Some

The only HIV vaccine to show promising efficacy in clinical trials stimulated an antibody-based defence in some individuals but not in others. Analysing patients’ samples from a large trial that took place in Thailand between 2003 and 2005, researchers have now identified a subgroup of study participants who express a human leukocyte antigen (HLA) allele linked to reduced risk of HIV infection after vaccination. The results of this latest analysis were published today (July 15) in Science Translational Medicine.

The highly mutable nature of HIV makes vaccine design particularly challenging. (See “Defeating the Virus,” The Scientist, May 2015.) Individual variation in immune response adds another layer of difficulty. The present study provides additional information on the range of possible immune responses to an HIV vaccine.

“Understanding why [the vaccine] appeared to work in some individuals and may not have worked in others is really paramount to moving the field closer to an effective [HIV] vaccine,” said Bruce Walker, director at the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, who was not involved in the work. “We don’t yet know enough about how to turn vaccine non-responders into responders, but this is an important first step.”

Rasmi Thomas of the Walter Reed Army Institute of Research in Silver Spring, Maryland, led the international team—including investigators from Thailand’s Ministry of Public Health—that analyzed the HLA class II alleles and HIV antibodies present after immunization in 760 trial participants.

The US Army-sponsored RV144 trial randomized more than 16,000 people in Thailand at risk for HIV infection to either the vaccine or placebo. The efficacy rate, reported in 2009, was 31.2 percent, yet those who expressed the DPB1*13 HLA allele appeared to be better protected from HIV infection, according to this latest analysis. Individuals with the DPB1*13 variant who also had high levels of immunoglobulin G (IgG) antibodies against a portion of the HIV envelope had the lowest rate of HIV infection following immunization in the trial. The efficacy rate in this subgroup was 71 percent. In other words, those individuals who received the placebo were three times more likely to become infected with HIV compared to those immunized individuals who expressed the apparently protective HLA allele.

“We already knew vaccine recipients that showed a certain type of IgG antibody response against a region of the HIV envelope were less likely to become infected with HIV,” Thomas wrote in an e-mail to The Scientist. “We now see that not everyone who produced this good type of antibody response was protected, but only those who had the DPB1*13 HLA variant.”

Specifically, higher levels of IgG antibodies against a 25 amino acid N-terminus portion of the HIV gp120 protein—encoded by the Env gene—conferred more effective immunity in those with the DPB1*13 allele. This portion of the highly variable protein, part of the virus’s outer envelope, is relatively conserved among the most common substrains of HIV.

A previous analysis of trial participants identified anti-Env IgA antibodies associated with reduced vaccine efficacy. This latest analysis further refined this non-responder subgroup, pinpointing individuals who not only generated these IgA antibodies but also expressed the DQB1*06 HLA allele.

Not everyone is so sure that lessons learned from the RV144 trial will advance HIV vaccine strategies. John Moore, who studies HIV-1 Env proteins at Weill Cornell Medical College in New York City is “not convinced that this kind of analysis helps in Env vaccine design.” Moore toldThe Scientist in an e-mail that he questions how antibodies of interest to the RV144 researchers might interact with Env to impede infection.

Walker, too, noted that immune responses may be specific to this vaccine. “This is one of the frustrations in the field,” he said. “We really don’t know if the correlates of risk for one vaccine are the same for another vaccine.”

But Thomas remains optimistic. “The task now is to work out what was different about the protective antibody response, in specifically people with DPB1*13, that could have caused the protection from HIV,” she said. “If this difference could be identified, it may be possible to design a vaccine that could induce an effective response in all individuals.”

Lessons on HIV vaccine efficacy based on genetic differences among individuals may also be extended to vaccine design for other diseases including dengue fever, malaria, and Ebola, added Thomas.

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Clinical Research Word Puzzle

Find 40 words used commonly in clinical research!

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