Drug Development & Testing


The development and testing of new drugs by the pharmaceutical industry is heavily regulated by the Federal Government. Because of the extensive animal and human testing required by the Federal Food, Drug and Cosmetic Act (FDCA), it takes seven to ten years of developmental work before a new drug is approved for market-ing, and estimates of the costs of development range from $100-$150 million, with an average of $120 million. Generally, pre-clinical (animal) studies require one to three years of work (average 18 months), and clinical testing may span a period of two to ten years (average five years). In most cases, animal and clinical testing can be carried out in a staggered developmental plan where sufficient animal testing is carried out in order to permit studies in man, of a similar or shorter duration, to proceed contemporaneously. Upon completion of animal and clinical studies, the data are submitted to the Food and Drug Administration (FDA) in the form of a New Drug Application (NDA) which then undergoes a review which may take up to seven years (average about 2 years).

History of the Federal Food, Drug, and Cosmetic Act (FDCA)

In 1936, the antibacterial properties of sulfanilamide were discovered and medical science was about to provide doctors with a wonderful new drug that would help control infection and save mankind from great suffering and death. However, before the finished product could be generally made available to doctors, Massengill Pharmaceutical Company had to find a way to get the sulfanilamide to dissolve in a suitable vehicle (i.e., solvent) so it could be administered accurately. In developing the final dosage form, scientists determined that a 10% sulfanilamide solution could be prepared in 70% diethylene glycol. The commercial product, Elixir Sulfanilamide, was distributed to the medical community without adequate toxicity testing in animals and without review by the FDA. As a result, before the product could be withdrawn from the market, diethylene glycol was implicated in the deaths of 105 individuals from kidney damage, and product liability law became inextricably linked with the development and distribution of pharmaceuticals.

The Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301-392) was promptly passed in 1938 in an effort to prevent further tragedies. The FDCA superseded the Federal Pure Food and Drug Act of 1906 as the basic food and drug law of the United States. The 1906 Act, which was concerned only with the purity of drugs, did not require that either safety or efficacy be established prior to marketing. This seemed adequate during the period from 1906 through the mid 1930s, when few new drugs were develop-ed and marketed. However, under the new FDCA, toxicity studies of new drugs were now required prior to marketing, and the active ingredients in the approved product would have to be listed on the label. Also, a New Drug Application (NDA) now had to be submitted by the sponsor and approved by the FDA, before a new drug could be promoted and distributed in the marketplace.

Since proof of efficacy was not required, extravagant claims for therapeutic activity were commonly made. Moreover, Section 201(g) of the Act provided a definition of drugs as:

articles intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease
in man or other animals and articles (other than
food) intended to affect the structure or any
function of the body of man or other animals.

During the early 1960s, thalidomide, a sleeping pill with no obvious advantage over existing drugs in its class, was marketed in Europe. After the introduction of this agent, it became apparent that the incidence of a relatively rare birth defect, phocomelia, was increasing in the population. Retrospective epidemiological research soon linked this epidemic of birth defects to the administration of thalidomide to the mothers, early in their pregnancies. The world was horrified by this tragedy which could possibly have been averted, had more thorough animal and human testing been carried out prior to marketing. Only the diligence of FDA investigator Dr. Frances Kelsy kept thalidomide from causing a similar tragedy in the United States.

1962 Kefauver-Harris Amendment

As a result of the thalidomide tragedy, in 1962, Congress passed the Kefauver- Harris Amendment to the FDCA, which required extensive animal pharmacological and toxicological testing before a drug could be tested in humans. The data from these studies must be submitted in the form of an IND (establishment of the IND 21 CFR 312.1) and approved by the FDA before clinical studies can begin. The amend-ment also required that manufacturers submit to the FDA “substantial evidence” of the unapproved (investigational) drug’s efficacy, as well as safety, in the form of an NDA. Therefore, in addition to safety, the manufacturer was now required to demonstrate efficacy (effectiveness), as well. “Substantial evidence” is defined by Section 505 of the FD&C Act as:

evidence consisting of adequate and well-controlled
investigations, including clinical investigations, by
experts qualified by scientific training and experience
to evaluate the effectiveness of the drug involved,
on the basis of which it could be fairly and responsibly
concluded by such experts that the drug will have
the effect it purports or is represented to have under
the conditions of use prescribed, recommended, or
suggested in the labeling thereof. FDCA [505(d)].

Adequate and well-controlled studies (investigations) are defined under 21 CFR 314.126.

Notice of Claimed Investigational Exemption for a New Drug or The IND

The requirements of the Food, Drug, and Cosmetic Act pose an interesting paradox. If the manufacturer is prohibited from distributing an unapproved drug within the United States as well as from exporting it to other countries, how can the clinical investigations required by the Act be conducted? The answer is that the unapproved drug is studied under a “Notice of Claimed Investigational Exemption for a New Drug” or IND.

The IND was established by the 1962 Kefauver-Harris Amendment to the FDCA, and is defined under 21 CFR 312. The document is filed with the FDA by the sponsor (usually the manufacturer). In general, the IND contains all of the scientific informa-tion known about the investigational drug to be studied. The data are presented according to a specified format.

In 1987, the format of the IND changed significantly. Although the information required to be filed in the IND remained virtually unchanged from previous formats, the numbering of the sections of the IND and the manner in which the data were grouped was rearranged. Copies of forms 1572 (Appendix IV), and 1573 (Appendix V), which have to be filed with the IND have also been enclosed as Appendices.

After the IND has been filed with FDA, the sponsor must then wait 30 days in order to give FDA an opportunity to review the IND. If the FDA has not contacted the sponsor with questions about the IND filing, the “initial introduction” study may be initiated on the 31st day. In some instances, the sponsor may request a waiver of the “30-day rule”. For example, if a sponsor is proposing to study a drug previously approved for a different indication in a new condition or disease. Since the safety of the drug in humans had already been established, if the new population of patients to be studied does not appear to be at greater risk than the previous population of patients, then the FDA may permit the new clinical investigations to proceed without delay, since only efficacy in the new condition must now be established. Furthermore, as long as the IND is “open” (functional), an annual IND progress report must be filed with FDA, generally on the anniversary date of the filing of the IND.

The New Drug Application or NDA

In 1938, the Federal Food, Drug and Cosmetic Act was enacted in order to ensure the safety of drugs marketed in the United States. Today an NDA may consist of hundreds of volumes of data which were compiled during animal and human (clinical) investigations. These data are submitted to the FDA as evidence of safety and efficacy in the form of a New Drug Application (NDA), as established by the FDCA and defined under 21 CFR 314.

The Food and Drug Administration reviews the submission and either grants approval of the application, states the application is approvable with the clarification of certain issues (21 CFR 314.110), or tells the sponsor of the NDA (i.e., usually the manufacturer, but not always) the reasons why it has determined that their NDA is not approvable (21 CFR 314.120)

Pre-Clinical (Animal) Testing of Drugs

Pre-clinical testing of new drugs can generally be divided into three types of studies: (1) animal pharmacology studies (includes screening tests and comparative tests with other drugs of known potency or activity), (2) animal toxicology studies, and (3) animal reproductive and teratology studies. Animal pharmacology studies determine what pharmacologic properties a drug has and which body systems the drug will affect.

Animal Reproductive and Teratology Studies

Prior to administering investigative drugs to women of childbearing potential, the effects of individual drugs on reproductive activity, fetal development, lactation and postnatal neonatal development must first be studied in animals. These studies have been divided into three segments. Segment I General Reproductive Performance, consists of dosing both male and female animals prior to mating and observing mating behavior during estrus. Following delivery, fetal deaths and malformations as well as lactation and neonatal development are compared to control values for the species under investigation. Segment II Teratology Studies, involve dosing pregnant female animals daily, beginning about one week after conception and continuing until the embryos have been removed from the mothers by Caesarian Section, prior to delivery. At this time, the embryos are examined for signs of toxicity and teratology. Segment III, Perinatal/Postnatal Studies, involve dosing pregnant female animals daily, during the last week of pregnancy and examining the newborn animals for abnormalities of development. Following birth, lactation, weaning behavior, growth and general appearance of the offspring are observed.

Clinical Testing of Investigational Drugs

The testing of investigational drugs in humans (clinical investigations / studies / trials) is divided into three phases. Prior to the initiation of clinical trials, the name of the investigator, his/her curriculum vitae, and a copy of the protocol must be added to the IND (i.e., sent to FDA for inclusion in the IND). In addition, the investigator must complete an FDA Form 1572 Statement of Investigator, included as Appendix IV) prior to Phase I and II studies, and a Form 1573 (Appendix V) for Phase III clinical research. Both the 1572 and 1573 Forms include the investigator’s statement that he/she will, pursuant to 21 CFR 56.102 (included as Appendix VII), obtain Institutional Review Board approval of the study prior to initiation, and that the investigatior will obtain Informed Consent from the patient, prior to drug administration. The basic elements of informed consent are described in 21 CFR 50.25.

Phase I Clinical Trial

The Phase I clinical trials involve the administration of the investigational drug to normal, healthy (i.e., those who do not have the medical condition/disease for which the drug is intended) male volunteers (the term subjects is also used). Females are usually excluded from this phase of study due to the possible teratogenic effect of a drug (e.g., thalidomide, DES, Accutane {isotretinoin}) although a woman who had undergone surgery to render her sterile might conceivably participate. The purpose of Phase I studies is to determine human tolerance to increasing single doses of the study drug followed by administration of the drug in multiple doses designed to simulate proposed administration to patients with the disease or condition for which the drug is being developed. As dosing approaches the anticipated therapeutic range, blood, urine, and stool samples are collected in order to determine information on absorption, distribution, metabolism, and excretion of the drug and its metabolites (i.e., the compounds into which the original {parent} drug is transformed while circu- lating through the body). An assessment of the rate and extent of a drug’s absorp-tion pattern, in comparison to a standard (either intravenous or an oral solution of similar dosage strength) is also conducted. This type of study is called a Bioavailability Study and forms the basis for establishing “bioequivalence” between two brands of the same generic drug. An Abbreviated New Drug Application (ANDA) demonstrating the bioequivalence of a generic brand of a drug in comparison to a brand name of the same agent may be approved by FDA on the basis of bioavailability studies, alone; costly, time-consuming safety and efficacy studies in patients may not be required.

Phase II Clinical Trial

Following the establishment of an acceptable, well-tolerated dosing regimen, the investigational drug enters Phase II clinical trials. This is the first time that the investigational drug is given to patients who have the disease/condition for which the drug is ultimately intended. Phase II clinical studies are designed to determine if the tolerated dose range established during Phase I has therapeutic properties in patients and if the adverse effects inherent in the drug occur at an acceptable level of severity and frequency. Initially, the side effect frequency is determined by comparing the experimental drug to a placebo (an identically-appearing inactive dosage form), under identical conditions. Subsequently, the experimental drug is compared to another active drug, usually a prototype drug with a similar side effect profile and often, one that is metabolized in a related manner. However, the FDCA requires only that the experimental drug be more effective than a placebo, not another active drug.

During Phase II, the typical investigational drug is administered to 200-300 patients for periods of time ranging from two weeks to three months. The short term studies are called early Phase II or Phase IIA studies, while the longer studies are called late Phase II or Phase IIB studies. Statistical analyses are performed on each clinical study individually, and on pooled data from several centers which have utilized the same research protocol. Adverse drug effects are collated and then tabulated by organ systems (i.e., cardiovascular, respiratory, renal, skin, etc.). These, in turn, are assigned a severity rating (mild, moderate, severe), and the apparent relationship between the adverse effect and the test drug is assessed as possible, probable, remote, or definite. Furthermore, the incidence of occurrence of the adverse effects is calculated and compared to similar data for patients who received placebo. Should the effectiveness of the drug appear encouraging and the side effect profile judged acceptable, then on the basis of these limited studies, the drug may be advanced to Phase III clinical investigations.

Phase III Clinical Studies

Phase III clinical studies are similar to Phase II studies, but they generally continue for a period of time ranging from several months to two-plus years. Moreover, after safety and efficacy have been generally established, the placebo or comparative group (i.e., control group) is usually dropped from the study design and the experimental drug continues to be studied on an “open” basis. This means that additional safety data will be collected without the benefit of a control group. Therefore, these data will be evaluated for frequency, severity and relationship to
test drug without the benefit of comparative data on another marketed drug or placebo.

Drug Development Services Available

  • IND Preparation and Filing
  • Phases I-III Clinical Protocols Developed and Studies Monitored
  • Preparation of Drug Brochures & Study Reports
  • Clinical Program Development
  • Interactions with FDA
  • Drug Safety & Labeling Issues
  • Specializing in Correlations Between Pharmacokinetics and Pharmacodynamics