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International Clinical Trials

State Side Transitions

The biotechnology and small pharmaceutical industry is growing rapidly in many regions outside the US, with numerous local governments in Europe and Asia supporting the creation of biotech incubators and corridors. Of course, many of these companies conduct Phase 1 clinical trials in their own resident environment because of their familiarity with local vendors, regional financial incentives and in-country health authority regulations.

However, as drug development progresses and the need arises to conduct larger studies, the local country or region may no longer provide an adequate patient base to enrol the trial. In addition, the company and its investors may begin to look ahead to the ultimate market potential of the drug and turn their attention to the US – the world’s largest market for pharmaceutical products.

Applications in the US

Regardless of where the investigational compound may have originated, to initiate and conduct clinical trials of an experimental product in the US, a sponsor must submit an investigational new drug (IND) application to the FDA for approval. This application provides the regulator with information necessary to determine whether the risks associated with the new drug or biologic and the proposed trial are reasonable for the human subjects participating in the study. It is comparable to the clinical trial application (CTA) submitted to health authorities in Europe and other parts of the world.

The IND application must contain sufficient information in three broad areas: clinical; non-clinical pharmacology and toxicology; and manufacturing. At all stages of product development, the safety of trial subjects is the FDA's primary concern.

Many non-US sponsors that have gathered clinical data in their own country are confident their IND will be successful because they have already demonstrated the safety profile of the drug. But, there are several additional criteria that also require attention in order to successfully transition a product into a Phase 2 dose-ranging trial and to gain approval for the conduct of a clinical study in the US.

Non-Clinical Data Requirements

During the preclinical drug development phase, a sponsor evaluates the drug's toxic and pharmacologic effects through in vitro and in vivo testing – including investigations on drug absorption and metabolism, as well as the toxicity of the drug and its metabolites. Typically, the FDA will require that sponsors:
  • Develop a pharmacological profile of the drug
  • Determine the acute toxicity of the drug in at least two species of animals
  • Conduct short-term toxicity studies, typically ranging from two weeks to three months, depending on the proposed duration of use for the substance being tested
In a CTA, the non-clinical summaries provided in the investigator's brochure are generally sufficient to gain approval for the conduct of Phase 1 trials. In the US, however, complete non-clinical study reports are usually required as part of an IND, and sponsors need to ensure that these reports are available in the required electronic format. This can present a challenge for those sponsors that have purchased or in-licensed their drug from another company or a university, because it is still not uncommon to find that the preclinical investigations were conducted many years prior and the reports exist only as paper documents. In these cases, a pre- IND consultation with the FDA is essential to reach agreement on the content and format of the reports that present the non-clinical data.

A second issue that often arises when non-US companies apply for an IND is the amount of toxicology data needed to support the proposed Phase 2 study. Deficiencies can be associated with the duration of the animal toxicology studies or relate to the doses used in supportive animal research. The doses in longer-term animal toxicology studies must be sufficient to support the higher doses and duration of the proposed dose-ranging trial in humans. A careful review of the data with a qualified toxicologist is highly recommended and may help avoid months of delay during the IND review process.

Chemistry and Manufacturing Data

The chemistry and manufacturing section of the IND application must include sufficient information to ensure proper identification of the investigational product – such as strength, quality and purity – so as to evaluate the potential risks to subjects. For example, data pertaining to the chemical composition, manufacturing methods, stability, reference standards and controls used for manufacturing the drug substance and product should be included. This information is assessed to ensure that the company making the application has an adequately controlled manufacturing process that can provide consistent and active batches of the drug.

Chemistry, manufacturing and controls (CMC) information is contained in the investigational medicinal product dossier (IMPD) that is submitted as part of a European CTA, and the format and content are essentially identical to the requirements of the IND. However, sponsors are wise to closely check the IMPD documentation for any changes to the manufacturing processes, or to suppliers or equipment, and also to make sure the most recent stability information is included in the IND submission.

Each IMPD focuses solely on the proposed trial; an IND has a broader scope and should contain sufficient information regarding the progress of the manufacturing development and scale up. It is interesting to note that as many applications are rejected for CMC issues as for clinical concerns.

Dose-Ranging Studies

It goes without saying that the protocols for proposed Phase 2 dose-ranging clinical trials should present convincing evidence that the product will not expose subjects to any unnecessary risk. In addition, full clinical study reports from any previous studies should be included, along with clear and concise summaries of safety data from any prior experience with the drug in humans.

Smaller biotech companies often prefer to dispense with the cost of writing a formal clinical trial report in order to apply their limited resources to planning the next study. While this is understandable, at the time of the filing of an IND, the reports need to be both complete and in an acceptable format in compliance with ICH guidance. Any safety issues that were identified in earlier research need to be described and addressed. For example, did subjects present with elevated blood pressure, gastrointestinal symptoms or liver enzyme elevation? To gain FDA approval, it is essential to explain how these adverse events will be prevented or monitored in the proposed Phase 2 trial, which will likely be of longer duration than the early-phase studies.

Streamlining the Process

Meeting the requirements for conducting trials in the US is an essential part of international clinical research. Yet, preparing an IND is more complex than regulatory submissions in many other parts of the world, and may be intimidating for those with little or no experience of dealing with the FDA.

Careful attention to detail and focusing the submission on the safety data collected to date can help ensure that sponsors meet the FDA's obligations. However, this is a labour-intensive task that often consumes the better part of three months. For many, the process is more effi ciently executed by selecting a regulatory consultant experienced with IND submissions from non-US companies.

Study timelines can often be speeded up by selecting a consultant that is integrated with the CRO conducting the trial. This offers the benefit of information-sharing among the regulatory and operational teams, and alignment of the final clinical protocol with the relevant requirements. A streamlined regulatory process and accelerated patient enrolment can be achieved when the sponsor, CRO and consultant work as partners with the common goal of initiating the trial with minimal delay.

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Roxanne Tavakkol is Vice President, Regulatory and Scientific Services, in the CRO Division at TKL Research. She has more than 25 years of industry experience, during which a key focus has been the development of regulatory strategy from proof-of-concept through product registration, as well as launch and lifecycle management. Roxanne has a successful registration track record encompassing peptide and small molecule drug products across numerous therapeutic areas. She has held executivelevel positions in biotech, and worked with both small and large pharma companies. In 2013, Roxanne joined TKL Research to expand its regulatory services department.
Roxanne Tavakkol
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