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Appendix I

New Drug DeveloPment

The initial one to three year phase of drug development begins in the research and development laboratories of pharmaceutical companies, universities and research institutes. New agents are purified from biological sources or are chemically synthesized, their properties characterized and pharmokinetic potential assessed in animals or in vitro tests. If it appears that an agent is not highly toxic and may have a potentially-beneficial effect against human disease, it is ready to enter the clinical trials phase.

At this point, the pharmaceutical company develops a clinical trials plan, or protocol, that outlines the scientific procedure which will be applied for human testing of the drug. These protocols must comply with national and international ethical standards that have been established for experiments involving human test subjects. If the pharmaceutical company intends to use the Canadian HIV Trials Network (CTN) to test an HIV/AIDS related drug, then the CTN assists the pharmaceutical company in the development of the clinical protocol. It is also at this point that the CTN encourages the company to consider compassionate release of the experimental drug and attempts to get a written commitment stating at which point in the trials release will be considered. The protocol is submitted to the Drugs Directorate as an Investigational New Drug (IND) submission. Clinical trials may proceed if the IND is approved.

Clinical trials generally take from two to ten years to complete. There are usually three clinical trial phases, although some phases may be combined or, depending upon results, rolled-over into the next phase. Phase I is conducted to establish basic safety tolerance in dose range, and phase II attempts to identify beneficial therapeutic activity. Phase III trials are initiated if the drug has been observed to be effective and not particularly toxic. At this point, usually hundreds and sometimes thousands of people are given the drug to see if it works for everyone and if it causes problems over a long period of time. Usually, at the beginning or during phase III, it will be known if the drug demonstrates some benefit and safety, and it is at this point that compassionate release of the drug is considered. However, it would not be unusual to delay compassionate release of the drug until after a sufficient number of participants have enrolled in the phase III clinical trials.

Following clinical trials, the research data is organized and submitted to the Drugs Directorate which then begins the new drug submission (NDS) review process. First the submission is screened to ensure that all the necessary data are present. There are two parallel review processes; one examines chemical and manufacturing data and the other examines the clinical trials data. This process, on average, now takes 17 months. The Drugs Directorate then makes a decision either to issue a notice of compliance, which is the marketing approval, or if the submission is deficient in some way a notice of non-compliance or a notice of deficiency is issued. The manufacturer has the opportunity to resubmit missing data, in which case the submission is examined again. The submission will receive a notice of compliance or the Drugs Directorate will withdraw the submission. The manufacturer may reapply, but they must start from the beginning of the new drug submission process after they have completed the necessary additional research.

The work of the Drugs Directorate is not finished when a new drug receives a notice of compliance (marketing approval); rather, the drug enters the post-marketing surveillance phase. Since the drug is now commercially available to a large number of people, incidences of toxic side effects may become more apparent. The pharmaceutical company is obliged to report drug side effects and the Drugs Directorate has the authority to reverse marketing approval.

It should be noted that the Drugs Directorate has a priority review policy. That is, the NDS review process will be accelerated, "fast-tracked," if the drug is intended for the treatment of immediately life-threatening and other serious disease where no comparable drug is marketed in Canada. Approximately five drugs are fast-tracked by the Drugs Directorate each year. For example, 3TC underwent accelerated review; the NDS submission was received 18 July 1995 and a notice of compliance was issued 11 December. Accordingly, this fast-tracked review took just under five months as compared to about 17 months for a normal review. Drugs that are fast-tracked receive the same review scrutiny as other drugs; the difference is that the NDS submission is given priority and "jumps the queue."

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