1. Basic & Clinical Evaluation of New Drugs
Mayyada Wazaify, PhD

2. Brain Massage! Answer is E (curve 5) Answer is A (curve 1)
Answer is C (curve 3)

4. The development and testing process required to bring a drug to market

5. DRUG DISCOVERY
Most new drugs or drug products are discovered or developed through one or more of six approaches:
1. Identification or elucidation of a new drug target .
2. Rational drug design of a new drug based on an understanding of biologic mechanisms, drug receptor structure, and drug structure
3. Chemical modification of a known molecule

6. DRUG DISCOVERY
4. Screening for biologic activity of large numbers of natural products, banks of previously discovered chemical entities, and large libraries of peptides, nucleic acids, and other organic molecules
5. Biotechnology and cloning using genes to produce peptides and proteins.
6. Combinations of known drugs to obtain additive or synergistic effects or a repositioning of a known drug for a new therapeutic use.
5. Biotechnology and cloning using genes to produce peptides and proteins. Efforts continue to focus on the discovery of new targets and approaches, from studies with genomics, proteomics, nucleic acids and molecular pharmacology for drug therapy. Significantly increasing the number of useful disease targets should be a positive driver for new and improved drugs.

7. Evaluation in Humans
The need for careful design and execution is based on three major confounding factors inherent in the study of any therapeutic measure-pharmacologic or nonpharmacologic-in humans

8. Evaluation in Humans Confounding Factors in Clinical Trials
1.Variable natural history of most diseases
(eg, spontaneous neoplasm remission) – to avoid errors, a crossover design is used
2. Presence of other diseases & risk factors (eg, life style) – to avoid errors, crossover design and valid methods of randomization are used
3. Subject & observer bias (placebo response) - to avoid, single-blind and double-blind design are used
THE VARIABLE NATURAL HISTORY OF MOST DISEASES Many diseases tend to wax and wane in severity; some disappear spontaneously, even, on occasion, malignant neoplasms. A good experimental design takes into account the natural history of the disease by evaluating a large enough population of subjects over a sufficient period of time. Further protection against errors of interpretation caused by disease fluctuations is provided by using a crossover design, which consists of alternating periods of administration of test drug, placebo preparation (the control), and the standard treatment (positive control), if any, in each subject. These sequences are systematically varied, so that different subsets of patients receive each of the possible sequences of treatment
THE PRESENCE OF OTHER DISEASES AND RISK FACTORS Known and unknown diseases and risk factors (including lifestyles of subjects) may influence the results of a clinical study. For example, some diseases alter the pharmacokinetics of drugs (see Chapters 3 and 4). Concentrations of a blood or tissue component being monitored as a measure of the effect of the new agent may be influenced by other diseases or other drugs. Attempts to avoid this hazard usually involve the crossover technique (when feasible) and proper selection and assignment of patients to each of the study groups. This requires obtaining accurate medical and pharmacologic histories (including use of recreational drugs) and the use of statistically valid methods of randomization in assigning subjects to particular study groups
C. SUBJECT AND OBSERVER BIAS Most patients tend to respond in a positive way to any therapeutic intervention by interested, caring, and enthusiastic medical personnel. The manifestation of this phenomenon in the subject is the placebo response (Latin, "I shall please") and may involve objective physiologic and biochemical changes as well as changes in subjective complaints associated with the disease. The placebo response is usually quantitated by administration of an inert material, with exactly the same physical appearance, odor, consistency, etc, as the active dosage form. The magnitude of the response varies considerably from patient to patient and may also be influenced by the duration of the study. Placebo adverse effects and "toxicity" also occur but usually involve subjective effects: stomach upset, insomnia, sedation, etc. Subject bias effects can be quantitated¾and minimized relative to the response measured during active therapy¾by the single-blind design. This involves use of a placebo as described above, administered to the same subjects in a crossover design, if possible, or to a separate control group of subjects. Observer bias can be taken into account by disguising the identity of the medication being used¾placebo or active form¾from both the subjects and the personnel evaluating the subjects' responses (double-blind design). In this design, a third party holds the code identifying each medication packet, and the code is not broken until all of the clinical data have been collected.

9. Cross Over Design

10. Randomization

12. The Food & Drug Administration (FDA)
The FDA is the administrative body that oversees the drug evaluation process in the USA and grants approval for marketing of new drug products.
The FDA's authority to regulate drugs derives from specific legislation (Table 5–3). If a drug has not been shown through adequately controlled testing to be "safe and effective" for a specific use, it cannot be marketed in interstate commerce for this use.
It is the responsibility of those seeking to market a drug to test it and submit evidence on its relative safety and effectiveness.

13. Jordan Food and Drug Administration
JFDA Established in 2004
Clinical Trials Unit (CTU)
The Clinical Research Law established in 2001
Seven Contract Research Organizations (CROs)
19 IRB, 12 of which are active

14. PRECLINICAL SAFETY & TOXICITY TESTING
to correctly define the limiting toxicities of drugs and the therapeutic index comparing benefits and risks of a new drug
the most essential part of the new drug development process
It is important to recognize the limitations of preclinical testing. These include the following: 1.    Toxicity testing is time-consuming and expensive. Two to 6 years may be required to collect and analyze data on toxicity and estimates of therapeutic index (a comparison of the amount that causes the desired therapeutic effect to the amount that causes toxic effects, see Chapter 2) before the drug can be considered ready for testing in humans. 2.    Large numbers of animals may be needed to obtain valid preclinical data. Scientists are properly concerned about this situation, and progress has been made toward reducing the numbers required while still obtaining valid data. Cell and tissue culture in vitro methods are increasingly being used, but their predictive value is still severely limited. Nevertheless, some segments of the public attempt to halt all animal testing in the unfounded belief that it has become unnecessary. 3.    Extrapolations of therapeutic index and toxicity data from animals to humans are reasonably predictive for many but not for all toxicities. Seeking an improved process, a Predictive Safety Testing Consortium of five of America's largest pharmaceutical companies with an advisory role by the Food and Drug Administration (FDA) has been formed to share internally developed laboratory methods to predict the safety of new treatments before they are tested in humans. 4.    For statistical reasons, rare adverse effects are unlikely to be detected.

15. PRECLINICAL SAFETY & TOXICITY TESTING
The goals of preclinical toxicity studies include:
identifying potential human toxicities;
designing tests to further define the toxic mechanisms; and
predicting the specific and the most relevant toxicities to be monitored in clinical trials
All drugs are toxic at some dose. Seeking to correctly define the limiting toxicities of drugs and the therapeutic index comparing benefits and risks of a new drug might be argued as the most essential part of the new drug development process. Most drug candidates fail to reach the market, but the art of drug discovery and development is the effective assessment and management of risk and not total risk avoidance. Candidate drugs that survive the initial screening and profiling procedures must be carefully evaluated for potential risks before and during clinical testing. Depending on the proposed use of the drug, preclinical toxicity testing includes most or all of the procedures shown in Table 5-2. Although no chemical can be certified as completely "safe" (free of risk), the objective is to estimate the risk associated with exposure to the drug candidate and to consider this in the context of therapeutic needs and duration of likely drug use.

16. "no-effect" dose: the maximum dose at which a specified toxic effect is not seen
The minimum lethal dose: the smallest dose that is observed to kill any experimental animal
The median lethal dose (LD50)-the dose that kills approximately 50% of the animals..
These doses are used to calculate the initial dose to be tried in humans, usually taken as one hundredth to one tenth of the no-effect dose in animals.
Presently, the LD50 is estimated from the smallest number of animals possible

17. Clinical Trials IND contains:
Once a drug is judged ready to be studied in humans, a Notice of Claimed Investigational Exemption for a New Drug (IND) must be filed with the FDA
IND contains:
(1) information on the composition and source of the drug,
(2) chemical and manufacturing information,
(3) all data from animal studies,
(4) proposed clinical plans and protocols,
(5) the names and credentials of physicians who will conduct the clinical trials, and
(6) a compilation of the key data relevant to study the drug in man made available to investigators and their institutional review boards.

18. Clinical Trials
Testing in humans is begun after sufficient acute & subacute animal toxicity studies have been completed
Chronic safety testing in animals is done concurrently with clinical trials
Usually 4-6 years of clinical testing
Ethical principles: Declaration of Helsinki, 1966
Approval of: sponsoring organization, FDA (in Jordan: JFDA), interdisciplinary institutional review board at facility

19. Clinical Trials Phase I:
- observes the effect of drug as a function of dosage
small number of healthy volunteers(25-50)
In some cases (cancer, AIDS, ie drugs with expected toxicity), patients with disease are used rather than normal volunteers
Nonblind (open)
Detect safety & pharmacokinetics
Done in research centers by clinical pharmacologists
In phase 1, the effects of the drug as a function of dosage are established in a small number (25-50) of healthy volunteers. Although a goal is to find the maximum tolerated dose, the study is designed to avoid severe toxicity. If the drug is expected to have significant toxicity, as is often the case in cancer and AIDS therapy, volunteer patients with the disease are used in phase 1 rather than normal volunteers. Phase 1 trials are done to determine whether humans and animals show significantly different responses to the drug and to establish the probable limits of the safe clinical dosage range. These trials are nonblind or "open"; that is, both the investigators and the subjects know what is being given. Many predictable toxicities are detected in this phase. Pharmacokinetic measurements of absorption, half-life, and metabolism are often done in phase 1. Phase 1 studies are usually performed in research centers by specially trained clinical pharmacologists

20. Clinical Trials Phase II:
Drug studied in patients with the target disease to determine efficacy
Number of patients is
Usually single-blind design with a placebo & positive control
Detects broader range of toxicities
Done in special clinical centers (eg, university clinics)
In phase 2, the drug is studied in patients with the target disease to determine its efficacy. A modest number of patients ( ) are studied in detail. A single-blind design is often used, with an inert placebo medication and an established active drug (positive control) in addition to the investigational agent. Phase 2 trials are usually done in special clinical centers (eg, university hospitals). A broader range of toxicities may be detected in this phase.

21. Clinical Trials Phase III Larger number of patients (e.g. Thousands)
Further study of safety & efficacy
Double-blind & crossover techniques
Investigators are specialists in disease being treated
If results meet expectations: application is made for permission to market the agent (NDA-new drug application)
FDA review of NDA may take up to 3 years
In phase 3, the drug is evaluated in much larger numbers of patients with the target disease¾sometimes thousands¾to further establish safety and efficacy. Using information gathered in phases 1 and 2, phase 3 trials are designed to minimize errors caused by placebo effects, variable course of the disease, etc. Therefore, double-blind and crossover techniques are frequently used. Phase 3 trials are usually performed in settings similar to those anticipated for the ultimate use of the drug. Phase 3 studies can be difficult to design and execute and are usually expensive because of the large numbers of patients involved and the masses of data that must be collected and analyzed. The investigators are usually specialists in the disease being treated. Certain toxic effects, especially those caused by immunologic processes, may first become apparent in phase 3.
If phase 3 results meet expectations, application is made for permission to market the new agent. Marketing approval requires submission of a New Drug Application (NDA) to the FDA. The application contains, often in hundreds of volumes, full reports of all preclinical and clinical data pertaining to the drug under review. The number of subjects studied in support of the NDA has been increasing and currently averages more than 5000 patients for new drugs of novel structure (new molecular entities). The duration of the FDA review leading to approval (or denial) of the NDA may vary from months to years. Priority approvals are designated for products that represent significant improvements compared with marketed products; in 2004, the median priority approval time was 6 months. Standard approvals, which take longer, are designated for products judged similar to those on the market¾in 2004, the median standard approval time was 12.9 months. In cases in which an urgent need is perceived (eg, cancer chemotherapy), the process of preclinical and clinical testing and FDA review may be accelerated. For serious diseases, the FDA may permit extensive but controlled marketing of a new drug before phase 3 studies are completed; for life-threatening diseases, it may permit controlled marketing even before phase 2 studies have been completed.

22. Clinical Trials
For serious diseases, the FDA may permit extensive but controlled marketing of a new drug before phase 3 studies are completed;
For life threatening disease, it may permit controlled marketing even before phase 2 studies have been completed;
Once approval to market the drug has been obtained, phase 4 begins…

23. Clinical Trials Phase IV (post-marketing)
Constitutes monitoring the safety of the new drug under actual conditions of use in large numbers of patients
Some rare toxicities are revealed (low incidence)
Orphan drugs:
drugs for rare diseases. Difficult to research, develop and market. FDA provides special assistance & grants for research of such drugs.
120 orphan drugs are approved for 82 rare diseases since 1983.
Once approval to market a drug has been obtained, phase 4 begins. This constitutes monitoring the safety of the new drug under actual conditions of use in large numbers of patients. The importance of careful and complete reporting of toxicity by physicians after marketing begins can be appreciated by noting that many important drug-induced effects have an incidence of 1 in 10,000 or less and that some side effects may become more apparent after chronic dosing. The sample size required to disclose drug-induced events or toxicities is very large for such rare events. For example, several hundred thousand patients may have to be exposed before the first case is observed of a toxicity that occurs with an average incidence of 1 in 10,000 (see Box: Case Study: Aspirin to COX-2 Inhibitors-From Discovery to Recall). Therefore, low-incidence drug effects are not generally detected before phase 4 no matter how carefully the studies are executed. Phase 4 has no fixed duration

24. Generic drug: a drug product that is produced by any pharmaceutical company after the patent of the originator drug is expired.

25. In Jordan
No. of Clinical Study protocols approved
No. of Clinical Study protocols submitted
Year 1 6
2002 3 5
2003
2004 2
2005
2006 9 10
2007