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PHARM-TOX - The Basics

WHAT IS PHARMACOLOGY AND TOXICOLGY?

Pharmacology is the study of the therapeutic properties of drugs or natural products. Toxicology is closely related, studying the harmful effects of chemicals, natural products, or drugs.

SOME DEFINITIONS

For the purpose of this tutorial, we will use the term drug to signify any compound, drug, natural product or biologic product, including gene therapy, that will be given to humans with the intention of treating or preventing disease.

A Pharm-Tox Study will refer to any type of study that seeks to determine the therapeutic and / or toxic effect of a drug using in vitro or animal studies.

In vitro refers to studies that are performed in the laboratory without the use of live animals or humans. Many times these studies involve cells or tissue grown in the laboratory.

In vivo studies refer to studies performed in live animals. Clinical studies refer to studies performed in humans.

Therapeutic Dose. The therapeutic dose is the amount of drug that provides the optimal beneficial effect. Something that is beneficial (or even essential) at one dose can become toxic at the wrong dosage. By combining in vitro studies and animal testing, Pharm-Tox studies hope to predict a drug dose that is both safe and effective before it is given to humans.

Metabolites. When a drug is taken into our body it is often metabolized (chemically altered) as our body attempts to breakdown the drug. Sometimes these breakdown products are not active, but in other cases they are pharmacologically active. In a number of cases, the drug we take is not active but it is our own body that changes it into a compound that is the active drug. In most cases, drugs are broken down into a variety of compounds some of which are beneficial, some have no effect, and some may be harmful.

Excretion. In addition to metabolizing drugs, our body will also attempt to remove drugs from the body. Many drugs are excreted in the urine by the kidneys or through bile produced in the liver and excreted into the stool. How fast the body excretes a drug will be important in determining how often a drug will need to be given. Pharm-Tox studies attempt to understand how a drug is excreted. Moreover, understanding this may also predict whether the dose of a drug should be altered in patients with liver or kidney problems.

Half-Life. We know that some drugs or metabolites may be very short lived while others can stay in the body for hours, days or weeks. When a drug is taken repeatedly, drug metabolites can build up over time leading to long-term effects. Half-life of a drug is a measure of how quickly a drug or metabolite is cleared from the body and is important in determining how much and how often a drug is to be given.

Organ Toxicity. Different organs metabolize drugs differently. As a result, some drugs can cause a problem in one organ while causing no ill effects in the rest of the body. Pharm-Tox studies in animals evaluate a wide variety of tissues to look for signs of damage before the drug is given to humans.

Dosing. As can be gleaned from the discussion above, drug metabolism and excretion is complex. Nevertheless, by studying the way drugs are processed by the body we can estimate both the amount of a drug (dose) and how often we need to give the drug (dosing schedule) to maintain the optimal amount of drug in the bloodstream to produce the desired therapeutic effect.

Sponsor. When a new drug or treatment is proposed to the FDA, the institution or companies proposing to develop the therapy is referred to as the Sponsor.

Investigational New Drug Application (IND). Before a new drug or treatment can be used in humans, the Sponsor must file an IND with the FDA. The IND outlines what is known about the drug, how the drug will be manufactured, Pharm/Tox data that has been performed, the clinical protocol under which the drug will be administered, and how the patients will be informed about potential risks. The FDA has 30 days to review the IND and if concerns are raised, they can place a hold on the IND and the Sponsor may not proceed until the FDA concerns are answered satisfactorily.

US Code of Federal Regulations. The CFR is a series of laws that define how the FDA operates, how drugs are to be analyzed prior to FDA approval, and how clinical trials are to be performed and monitored, and how patients should be protected from research associated risks. The CFR applies to both academic researchers and drug companies, these regulations have legal consequences for those who fail to comply.

WHEN SHOULD PHARMACOLOGY OR TOXICOLOGY STUDIES BE PERFORMED?

A Pharmacology or Toxicology study should be performed when laboratory evidence and preliminary animal studies have identified a drug with significant promise for the treatment of disease. The Pharm/Tox studies are a bridge that helps justify the use of the drug in humans and estimate the dose and dosing schedule for humans receiving the drug.

DO SIDE EFFECTS IN PHARM/TOX STUDIES MEAN THAT A DRUG CANNOT BE ADMINISTERED TO HUMANS?

Pharm/Tox studies are designed to determine the short and long-term side effects from a drug. Just because a drug has some side effects does not mean it cannot be used in humans. The FDA and the developer of the treatment must agree that the known or potential risk of a treatment is outweighed by the potential benefit (i.e. the risk: benefit ratio). For example, if a drug caused temporary hair loss it would not be acceptable as a new treatment for headaches. In contrast, chemotherapy that is used to treat cancer often causes hair loss but the risk of that side effect may be acceptable to a patient due to the serious nature of the cancer. What is required is disclosure of that risk to the patient so they may make an informed consent about whether to receive the treatment. There is a legal requirement for information about known or potential side effects to be disclosed, regardless of whether the treatment is investigational or already approved by the FDA.

WHO DECIDES IF A DRUG IS SAFE TO ADMINISTER TO HUMANS?

Once Pharm/Tox studies have estimated the potential side effects associated with a drug, the Sponsor must interpret the findings of the Pharm/Tox studies. If they believe the risk: benefit ratio favors moving the drug to human clinical trials they must complete an Investigational New Drug Application (IND) and submit this to the FDA. In the IND, the investigator must justify why they believe the Pharm/Tox study supports moving the drug into the clinic. They must also provide the detailed reports from the study for the FDA to review.

The FDA will then review the results presented in the IND and make an independent determination as to whether it is reasonable to begin a clinical trial to study the drug in humans. If the FDA has questions after reviewing the IND, they can place the clinical trial on hold until the questions are resolved. The FDA is also free to audit the records of the Pharm/Tox studies and samples from the study must be maintained for FDA review.

For human clinical trials, an independent Institutional Review Board that serves to protect patients from risks associated with research must also review the study. The function of this Board is described in the Code of Federal Regulations and must assess the risk, monitor the conduct of the trial, and ensure patients give informed consent before treatment can begin.

WHAT SHOULD SPONSORS CONSIDER WHEN DESIGNING A PHARM/TOX STUDY?

When developing a drug for human use, one must consider how the drug must be given to maximize effectiveness. For example, will the drug be given as a one-time dose, or will it be given repeatedly over many years? Knowing how much, how often and for how long a drug will be given are critical questions when designing a Pharm/Tox study. Since Pharm/Tox studies can be very expensive, it is well worth the effort and expense of performing preliminary experiments aimed at identifying the potential dose and dosing schedule to be used in the Pharm/Tox study so the optimal information is collection to support the dose that will be used in humans.

A Sponsor is also well advised to develop a Pharm/Tox study with input from the FDA prior to initiating the study. The Sponsor should carefully determine what critical studies are required then contact the FDA to discuss the proposed Pharm/Tox study. It is better to identify concerns from the FDA before the costly and time-consuming Pharm/Tox study is initiated to minimize the chance that the study will be inadequate or insufficient to support the IND.

There are a number of options for discussing drug development with the FDA. A Pre-Pre IND call is an informal, non-binding discussion that allows the Sponsor to provide the basic premise and supporting results that warrant drug studies in humans. A Pre-IND meeting is a more formal meeting in which the Pharm/Tox studies and the proposed clinical trial design will be discussed with a variety of FDA officials. In both cases, the FDA may make suggestions regarding the design of the Pharm/Tox study. Additional studies, or study modifications, are not uncommon and is why the FDA should be approached prior to conducting the study.

WHAT ARE SOME SPECIAL CONSIDERATIONS WHEN DESIGNING PHARM/TOX STUDIES?

Many drugs can cause birth defects if given during pregnancy, so drugs that may be taken in women of childbearing age may require special testing. Children metabolize drugs differently than adults, so drugs that will be administered to children will likely require special testing. Importantly, certain classes of drugs that increase the risk of cancer causing mutations will require special risk assessments.

WHO PERFORMS PHARM/TOX STUDIES?

Pharm /Tox studies are generally not performed in research laboratories but conducted in specialized centers with specific expertise in these studies. In general, Pharm/Tox studies are conduced under Good Laboratory Practices (GLP). The requirements for GLP work are described in the US Code of Federal Regulations (21 CFR part 58).