Evolution of a NewEvolution of a NewMedicationMedication

So you have an idea for a new drug that could help people….

It is not as simple as manufacturing, putting it a bottle and sitting on the shelf.

The procedure is complicated, time consuming and expensive.

The Pharmaceutical Industry is BIG Business.

Many people spend a large portion of their income on medications each month

Americans will spend $100 billion on prescription drugs this year, double what they spent six years ago.

Under current law, all new drugs need proof that they are effective, as well as safe, before they can be approved for marketing.

But it's important to realize that no drug is absolutely safe.

There is always some risk of an adverse reaction.

It's when the benefits outweigh the risks that the Food and Drug Administration considers a drug safe enough to approve.

In fact, it was little more than 30 years ago that U.S. drug law first embraced the idea of risk vs. benefit that is now the key to new drug approval.

Providing evidence of safety before marketing was first required by the Federal Food, Drug, and Cosmetic (FDC) Act in 1938, but not until the

Kefauver-Harris Drug Amendments of 1962 did firms also have to show a drug's effectiveness before marketing.

FDA's decision whether to approve a new drug for marketing boils down to two questions:

Do the results of well-controlled studies provide substantial evidence of effectiveness?

Do the results show the product is safe under the conditions of use in the proposed labeling?

Safe, in this context, means that the benefits of the drug appear to outweigh its risks.

The process starts with a drug sponsor, usually a pharmaceutical company, seeking to develop a new drug it hopes will find a useful and profitable place in the market.

Before clinical testing begins, researchers analyze the drug's main physical and chemical properties in the laboratory and study its pharmacologic and toxic effects in laboratory animals.

If the laboratory and animal study results show promise, the sponsor can apply to FDA to begin testing in people.

 

It is a mistake to rely on the assumption that the patient would not have become well in the absence of intervention.

Pasteur’s rabies vaccine did not require a controlled trial because the antecedent was unmistakable (being bitten by a rabid animal) and the disease was invariably fatal.

Survival demonstrated the treatment’s efficacy because neither placebo effect nor spontaneous remission were reasonable alternative hypotheses.

The development of psychotropic agents in the 1950s met with considerable skepticism.

It was argued that apparent benefits could be due to suggestion or spontaneous remission.

This led to the rapid adoption of the randomized, placebo-controlled trial.

Both treatment groups were, within chance sampling fluctuations, equivalent with regard to placebo effect and spontaneous remission, providing an elegant control.

Other alternative hypotheses such as experimenter or patient bias or a confound of patient differences with treatment method were countered by double-blinding and randomization.

Understanding Controls In a controlled trial, patients in one

group receive the investigational drug. Those in a comparable group--the

controls--get either no treatment at all, a placebo (an inactive substance that looks like the investigational drug), a drug known to be effective, or a different dose of the drug under study.

What is a placebo?

A placebo is an inactive pill, liquid, or powder that has no treatment value.

In clinical trials, experimental treatments are often compared with placebos to assess the treatment's effectiveness.

In some studies, the participants in the control group will receive a placebo instead of an active drug or treatment.

What is a control or control group? A control is the standard by which

experimental observations are evaluated. In many clinical trials, one group of

patients will be given an experimental drug or treatment,while the control group is given either a standard treatment for the illness or a placebo.

Usually the test and control groups are studied at the same time.

In fact, usually the same group of patients is divided in two with each subgroup getting a different treatment.

That is the best way to be sure the groups are similar.

It's important that treatment and control groups be as similar as possible in characteristics that can affect treatment outcome.

For instance, all patients in specific groups must have the disease the drug is meant to treat or same stage of the disease.

Methods of Comparability

Paired ResearchPaired Research Carefully pair each person in the Carefully pair each person in the

treatment group with a control patient treatment group with a control patient who has closely matching who has closely matching characteristics. characteristics.

This method is rarely used today This method is rarely used today because even in the best of because even in the best of circumstances, it's difficult to match circumstances, it's difficult to match pairs of patients for the myriad factors pairs of patients for the myriad factors that could have a bearing on results. that could have a bearing on results.

Randomization Patients are randomly assigned to either

the treatment or control group, rather than deliberately selected for one group or the other.

When the study population is large enough and the criteria for participation are carefully defined, randomization yields treatment and control groups that are similar in important characteristics.

Because assignment to one group or another is not under the control of the investigator, randomization also eliminates the possibility of "selection bias," the tendency to pick healthier patients to get the new treatment.

“Blind”Study

In conjunction with randomization, a design feature known as "blinding" helps ensure that bias doesn't distort the conduct of a study or the interpretation of its results.

Single-blinding consists of keeping patients from knowing whether they are receiving the investigational drug or a placebo.

In a double-blind study, neither the patients, the investigators, nor the data analysts know which patients got the investigational drug.

Only when the closely guarded assignment code is broken to identify treatment and control patients do the people involved in the study know which is which.

FDA reviewers assess the benefit-to-risk relationship

The human studies also generate information that will be in the drug's professional labeling, the guidance approved by FDA on how to use the drug. This is the package insert that accompanies a drug in all shipments to physicians and pharmacies.

What is a clinical trial?What is a clinical trial? A clinical trial is a research study to answer

specific questions about vaccines or new therapies or new ways of using known treatments.

Clinical trials are used to determine whether new drugs or treatments are both safe and effective.

Carefully conducted clinical trials are the fastest and safest way to find treatments that work.New therapies are tested on people only after laboratory and animal studies show promising results.

What is a protocol? All clinical trials are based on a set of rules

called a protocol. A protocol describes what types of people

may participate in the trial; the schedule of tests, procedures, medications,and dosages; and the length of the study.

While in a clinical trial,participants are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment.

Clinical trials of experimental drugs proceed through four phases:

In Phase IPhase I clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

Phase 1 Number of Patients: 20-100

Length: Several monthsPurpose: Mainly safetyPercent of Drugs Successfully Tested:

70 percent70 percent

In Phase IIPhase II clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

Phase 2 Number of Patients: Up to several hundred

Length: Several months to 2 yearsPurpose: Some short-term safety but mainly effectivenessPercent of Drugs Successfully Tested:

33 percent33 percent

In Phase IIIPhase III studies, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

Phase 3 Number of Patients: Several hundred to

several thousandLength: 1-4 yearsPurpose: Safety, dosage, effectivenessPercent of Drugs Successfully Tested:

25-30 percent25-30 percent

Phase IVPhase IV studies are done after the drug or treatment has been marketed. These studies continue testing the study drug or treatment to collect information about their effect in various populations and any side effects associated with long-term use.

Of 100 drugs100 drugs for which investigational new drug applications are submitted to FDA, about 70 will successfully complete phase 1 trials and go on to phase 2;

about 33 of the original 10033 of the original 100 will complete phase 2 and go to phase 3; and

25 to 30 of the original 10025 to 30 of the original 100 will clear phase 3

about 20 of the original 10020 of the original 100 will ultimately be approved for marketing.

More than 80 medications are in development to treat mental illnesses, including 18 for depression, 15 for schizophrenia and 16 for anxiety disorders, according to the Pharmaceutical Researchers and Manufacturers of America (1998).

Last year, the FDA approved 66 new drugs, 24 of which contained never-before-sold ingredients.

Ten were ``priority'' drugs, or potential breakthroughs - and they still speeding through the FDA.

The median approval time was six months, unchanged from previous years.

One, a major advance in leukemia therapy called Gleevec, set a record when it won FDA approval in less than three months.

Median approval time for the other, so-called ``standard'' drugs was 14 months.

That's not as fast as the 11.6 months such drugs spent at FDA in 1999 but a little faster than the 15.6 months FDA spent such products in 2000, FDA records show.

Drug industry is Big Drug industry is Big BucksBucks

And it does not And it does not always go as plannedalways go as planned

Cancer Drug “The FDA shocked Wall Street in late

December by rejecting the marketing application for Erbitux, saying ImClone failed to provide adequate data to support its conclusion the drug was effective among patients with colorectal cancer who had failed earlier treatment with Pharmacia Corp.'s Camptosar.

Erbitux…….. The FDA had previously told ImClone it

would have to conduct new clinical trials of the medicine to provide the missing clinical data, a fact that ImClone failed to disclose in a Dec. 28 news release announcing the agency had spurned the application.

Such new trials could delay approval of Erbitux by as much as two years, according to some industry analysts who had previously forecast the medicine could become a blockbuster with annual sales of over $1 billion.

Erbitux……

The House panel said last week it would seek records from the FDA, ImClone and Bristol-Myers to establish the validity of ImClone's research into Erbitux.”

Oncolytics seeks clinical trials for cancer drug TORONTO, Jan 24 (Reuters) - Oncolytics Biotech Inc.

said on Thursday it filed an application to initiate clinical trials for Reolysin as a treatment for recurrent malignant glioma, the most aggressive form of brain cancer.

In Phase I, patients with a variety of malignant gliomas will be enrolled, whereas the Phase II trial will focus on patients with recurring malignant gliomas.

Forest gets conditional U.S. approval for Lexapro

NEW YORK, Jan 24 (Reuters) - Drugmaker Forest Laboratories Inc. on Thursday said it had received conditional U.S. regulatory approval to market its new antidepressant Lexapro, a second-generation version of Celexa, Forest's top-selling drug.

New York-based Forest said it expects to begin marketing Lexapro by mid-year. It said it filed for approval of the drug in March 2001.

The company has said clinical trials proved Lexapro to be safer and more effective than Celexa, which had sales of more than $980 million in 2001.

Forest said it received an ``approvable letter'' from the U.S. Food and Drug Administration.

Such letters are normally issued when the agency is prepared to approve a drug based on its safety and efficacy but is engaged in final negotiations over labeling or manufacturing with the drugmaker.

Patent

Patent expirations on major drugs have stifled Bristol-Myers' drug sales, and deeper cuts in future sales are expected. Cancer drug Taxol and anti-anxiety treatment BuSpar already face stiff competition from generic competitors, and copycat versions of diabetes treatment Glucophage are expected to hit the market in 2002.

NEW YORK, Jan 24 (Reuters)

Bristol-Myers, the world's No. 5 drugmaker, warned earnings will be off 10 percent to 15 percent in the first quarter on slowing sales of key drugs. And it affirmed its forecast for 2002 earnings to fall to a range between $2.25 and $2.35 per share, down from its 2001 profit of $2.41 a share.

``Bristol-Myers is struggling with products coming off patent, and it looks like that will hurt them for the next several quarters,'' said analyst Richard Lawrence of Parker/Hunter Inc.

Generics Merck-Medco says that recent research

has found that although 83% of Americans believe that generics are generally as safe and effective as brand-name drugs and that they cost less, they represented only 41% of overall prescription drug sales in 1998.

The US National Consumers League has launched a public education campaign to encourage consumers to ask their physicians and pharmacists about generic drugs.

Watson says FDA approves generic Glucophage

CORONA, Calif., Jan 24 (Reuters) - Drugmaker Watson Pharmaceuticals Inc. said on Thursday it received final approval from the U.S. Food and Drug Administration (FDA) to make and market a generic form of Glucophage, the world's top- selling diabetes medicine.

Over the Counter Unlike Rx drugs, OTC medicines are

usually used to treat self-limiting conditions-that is, problems that will eventually go away on their own.

Therefore, OTC drugs are focused more on controlling symptoms of various ailments, such as aches, pain and colds.

At present, there are more than 300, 000 OTC products on the market, and more are being added every day.

The phenomenal growth in the OTC market can be attributed to genuine developments in pharmacology, as well as to the public's growing insistence on having a "ill for every ill."

Even though they are not as potent as Rx medicines, OTC drugs nevertheless have powerful main effects and often serious side-effects.

Herbals Herbal medications do not have to

meet the specifications of FDA The safety and validity of these

remedies is controversial. More later on this subject……