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International Clinical Trials

Factoring in Feasbility

Anna Ravdel and Svetlana Timofeeva at Synergy Research Group look at the importance of feasibility assessment for successful clinical studies

A well-researched feasibility study is one of the key success factors for any clinical study; it is critical for both ‘go/no go’ and ‘how to’ decisions. Feasibility studies in clinical research answer many questions and can be conditionally divided into three groups: regulatory feasibility, logistics feasibility, and clinical feasibility.

Regulatory feasibility assesses issues such as regulatory processes and timelines; the likelihood of getting regulatory approval in a certain country; possible thresholds during the regulatory process and ways to overcome them; insurance and reimbursement policies and practices; and so on.

Logistics feasibility assesses issues related to the handling of clinical trial materials, such as possibilities, processes and timelines for organising import and export; customs procedures; storage and distribution of clinical trial materials within a certain country; local purchase of clinical trial materials; and use of local labs.

Clinical feasibility assesses epidemiology in different geographic locations; standards of care in different countries; number and geographic distribution of study sites; expected enrolment rates; and the experience of investigators in certain fields of medicine.

In order to make an educated decision regarding the geographical distribution of study sites, it is vital to perform all three kinds of feasibility assessment before moving forward.

PROFESSIONAL EXPERTISE

Each kind of feasibility assessment should be carried out by corresponding professionals, such as the regulatory experts who must be involved in the regulatory feasibility process. Logistics feasibility assessment should be performed by, among others, regulatory specialists, logistics professionals, and pharmacists with knowledge of local medication availability and purchase methods. Clinical feasibility should be performed by personnel with a medical background and detailed knowledge of local health systems, key opinion leaders and local physicians. At every stage of the feasibility assessment, it is advisable to seek the assistance of local personnel, instead of relying solely on general knowledge, the internet and literature research of feasibility and regulatory professionals from central offices of different organisations.

Whether planning a global study involving numerous sites or choosing one or two countries for a smaller clinical study, many questions must be answered in order to ensure that the best decisions are made during the start-up phase of the study.

REGULATORY FEASIBILITY ASSESSMENT

For each country in question, it is necessary to know the regulatory process, including both the official timelines for obtaining approval as well as the real ones based on previous experiences. Sometimes fast enrolment compensates for delays in the regulatory process, and it is still worthwhile to operate in countries with long regulatory approval processes; these countries will later yield more patients than countries with a fast regulatory track but few patients. Many countries with lengthy regulatory processes have a sufficient number of patients willing to participate in clinical trials; they may also have experienced investigators to conduct the studies and a suitable infrastructure. However, this strategy will not work if the number of patients to be enrolled is small and the global recruitment period has closed by the time that the ‘fast recruiter’ enters the game.

In addition to the timelines of obtaining study approval, other requirements and local conditions that can influence the overall start-up period should be taken into consideration.

Specifics of Document Preparation

In some countries, regulatory bodies require certain documents to be translated. This means that if changes are made to the protocol or investigator brochure, informed consent form or other documents during the submission package preparation, those changes must be translated, and this can delay the submission process. Changes submitted to the regulatory authorities after the general submission is completed may be regarded as an amendment and could therefore lead to an extension of approval timelines and an increase in regulatory fees.

Other Local Particulars

Regulatory bodies in some countries take a two-month holiday during the summer, and submission packages are not accepted during this period. General vacations (those not specific to regulatory bodies, such as Christmas and New Year) can also prevent document collection and submission for two to three weeks in winter. All this must be taken into consideration; if your start-up activities fall during the holiday period, the date of the first patient in will automatically be postponed.

Regulatory Costs

In some countries, the regulatory process involves obtaining local insurance in addition to the sponsor’s general insurance. The cost of this per patient may vary, depending on the study phase and the protocol. If the number of patients is high, insurance premiums can substantially increase overall study costs, so it is worth checking this information during the initial country feasibility study.

Documents Required for Submission

Regulatory requirements for the submission package content differ from country to country. In some cases, countries require the complete summary of the main product characteristics package or ask for the results from previous studies conducted in other countries. When part of the data is deficient or missing, it is advisable to make a preliminary check of the existing documents before submission. Regulatory specialists from each country will review the documents and advise on further steps. Consultancy with a representative of the local health authorities can be solicited, in order to save time and costs in the future.

LOGISTICS FEASIBILITY ASSESSMENT

Logistics issues are no less important than regulatory ones. While you may receive regulatory approval quickly, subsequent logistics difficulties can cause serious delays and disrupt the entire study schedule. The following issues are among those to be taken into account during the logistics feasibility check:

  • Import and export procedures
    • Verify the need for import permits for different clinical trial materials and the number of such permits required throughout the study (whether it is one for the entire study or one for each shipment)
    • Check the specific restrictions on import, storage and distribution of clinical trial materials (such as controlled substances)
    • Clarify the customs clearance procedures and fees. In some countries, customs fees reach up to 40 per cent of the customs value and can add a substantial amount to the overall study costs – Examine the export procedures for biosamples, unused clinical trials materials or devices (for example, the requirement of licenses)
  • General study logistics
    • Choose the best approach for the import and distribution of clinical trial materials – that is to say, select a centralised approach (bulk shipments to the country’s central depot with subsequent distribution to the sites), or a decentralised approach (direct shipments from the sponsor’s central facility or distribution centre to the sites) based upon the situation
    • Select a courier company in each participating country (the company used for shipment of the refrigerated investigational product in one country might not be appropriate in another, even if represented there)
    • Investigate the possibilities of local purchase and the costs of clinical trial materials
    • Obtain information on re-labelling requirements
    • Make decisions on the handling of unused clinical trial materials at the end of the study (possibilities include local destruction or exportation), and investigate ways to organise this

While regulatory and logistics feasibility studies assess the real, ‘objective’ situation, a large part of clinical feasibility research necessarily relies on subjective information: questionnaires completed by potential investigators. We should, therefore, interpret this information with great care.

REALITY CHECK

It is no secret that a significant percentage of studies are substantially behind schedule due to unexpectedly low enrolment. Although there is no way to completely eliminate these delays, it is possible to cut them through pre-study activities.

Most companies conducting clinical trials share this thinking and perform feasibility studies either during the proposal preparation stage or during start-up activities. Nevertheless, in many cases, the results are not a realistic assessment. The question is, therefore, how to conduct a trustworthy clinical feasibility assessment.

FORECASTS

There are different thresholds during the process, and various means to reduce their number and influence. On the one hand, pharmaceutical and biotech companies want to have a real picture; on the other hand, during the RFP process sponsors often ask for proposals allowing them to compare ‘apples with apples’, providing timelines, countries and number of sites to the CROs participating in the bidding process. In some cases, those expectations are unfeasible, but if the CRO wants to participate in the bid it should adhere to them. Although during the RFP process feasibility assessment is sometimes not performed at all, or performed very briefly (proposal preparation timelines may not allow for conducting the fullscale assessment), at the end the winning bid is used as a budget, and the timelines become a part of the contract. Over the course of the study, it may become clear that previous forecasts in the contract are not viable, and a change order will need to be issued; this will push up study costs and increase the number of overdue studies.

One way to solve this problem is, wherever possible, to consider CROs not as case-by-case service providers, but as partners participating in the studies. The CRO can thereby be entrusted to carry out the initial feasibility assessment and draw up forecasts as the basis for their proposal.

Regarding the difficulties in comparing bids with different forecasts, the following three-fold approach can be considered:

  • RFP dispatch with the same forecasts
  • Choice of two or three finalists
  • A second round of bidding involving data as proposed by CROs

If this approach cannot be used due to the strict timelines on the study commencement, additional feasibility checks may be carried out after the CRO has been chosen. Start-up activities can begin under the Letter of Intent while a thorough feasibility study is being performed. This tactic may cause immediate changes in the study planning, but it will reduce the chance of further unexpected alterations throughout the project.

DEADLINES

In many cases, timelines for feasibility assessment are very tight; feasibility groups may have to find dozens of sites and hundreds of patients in one week. Though both the sponsor and the CRO understand that this haste might reduce the accuracy of the results, it is sometimes inevitable.

One of the ways to overcome this pitfall is to use a reliable database for a quick feasibility check. By exploiting such databases, a CRO can prepare and implement a quick feasibility plan (see Figure 1), benefitting from the following features:

  • Rapid access to epidemiology data that provides information on the suitability of different regions
  • Access to data on potential investigative sites in the region that can provide contact information for the dispatch of feasibility questionnaires
  • Access to data on referral sites in the areas of interest, giving insight into the possible existence of additional sources of patients
  • Information on the previous experiences of the sites, giving insight into the expected enrolment rates

RELIABILITY

The most vulnerable part of the feasibility assessment is the preparation, dispatching and collection of the feasibility questionnaires, and, above all, the level of the reliability of the information received from the potential investigators. There are several different factors that should be taken into account in order to reduce the negative impact of subjective assessment. Firstly, investigators tend to be optimistic and overestimate recruitment potential. This overestimation can be rooted in various factors, including previous experience when the number of competitive studies was low, lack of time and information, and a desire to be commissioned. This bias should not be overlooked. The method of adjustment of patient numbers will vary depending on the therapeutic area and earlier practice but, should always be done.

Secondly, feasibility questionnaires should be composed to include all the necessary questions and no others. Investigators participate in numerous clinical trials and simultaneously receive a lot of questionnaires from different companies. Completion of these questionnaires is time consuming, but many investigators try to complete them quickly. Consequently, in a long questionnaire, investigators might give less attention to each separate question, and the accuracy of the completed questionnaire will be affected. Of course, a long questionnaire is occasionally a necessity, but in that case, potential inaccuracy should be taken into account in the analysis.

In some circumstances, feasibility is done on a draft study protocol; further changes to the document can lead to a new expected enrolment rate. If the protocol changes are substantial, it is advisable to carry out additional feasibility checks, as forecasts can otherwise differ significantly from the final results.

Sometimes, however, feasibility assessment has to be carried out without a protocol, based on vague inclusion or exclusion criteria. In these cases, it is difficult for investigators to conduct a proper assessment of potential enrolment levels and there is no way to obtain concrete results. The estimated number of patients should be based on previous experiences and on results received from the database, or the calculated entire assessment should be redone using the definite protocol.

Investigators often rely on their previous experiences when completing feasibility questionnaires. This information is very important, and comparing results with those from the CRO database and historical data is essential for the analysis. Past results, however, do not always guarantee future repetition, as the situation may change, perhaps due to the growth of the competitive studies or new regulations. In addition to the comparative check therefore, old information should be factored in to reflect these changes.

Finally, during the feasibility report preparation and the process of estimating the recruitment period and the number of sites, it is important to remember that not all the sites will be open simultaneously. The recruitment time for some sites might be about one month less than for others, so it is advisable to mitigate the risk of under-enrolment by adding extra months or sites.

CONCLUSION

Feasibility assessment is vital for clinical trial planning, with clinical, regulatory and logistics checks all an essential part of the process. It is equally essential for adjustments to be made to the number of patients proposed by the investigators of a successful feasibility assessment. This adjustment should be made using all the data available in order to minimise the bias of the forecast, as mistakes in the feasibility assessment can lead to a dramatic increase in study costs and duration.


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Anna Ravdel is Director of Business Development at Synergy Research Group (SynRG). Anna graduated from the University of Manchester with an MBA in 2001. Prior to joining SynRG in 2009, Anna worked as a Director of Business Development at Evidence Clinical and Pharmaceutical Research, and Director of Business Development, Eastern Europe, at Worldwide Clinical Trials. In her current position, Anna’s responsibilities include elaboration of business development strategies, key goals and methods to achieve them. In cooperation with operational departments, Anna is in charge of overall clients’ proposals development, including active participation in the performance of feasibility assessment studies. Email:

Svetlana Timofeeva is Director of Clinical Operations at SynRG. Svetlana gained her medical experience as a Cardiologist at the State Research Center for Preventive Medicine in Moscow. She has been involved in the clinical trial arena since 1999. Svetlana is the author of more than 50 articles published in Russian and international scientific magazines. At SynRG, Svetlana’s duties include strategic planning of clinical operations. She is in charge of all projects conducted by the company, providing guidance and leadership to the clinical operations team. Svetlana also supervises the performance of the regulatory affairs department. Email:

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