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Ten Mistakes Companies Make with Investigational New Drug Applications (INDs)/Clinical Trial Applications

Dr. Speid is available to discuss these and other matters of a regulatory affairs nature at Tel: 858 793 1295.

INDs are high stakes applications. It is often the first application that a senior management team will submit. Poor quality work will lead to the IND being placed on clinical hold. It will also reflect very poorly on the company for the future of that company. The following is a list of the top ten mistakes that companies with INDs/Clinical Trial Applications.  

MISTAKE NUMBER 1: Companies often focus on the date of filing rather than the date of clearance.    

Many companies rush to file the IND because they want to be able to tell their Board of Directors and the investors that the IND has been filed. That same company will then take months and even sometimes years to initiate the clinical trial after the IND has been cleared.  

ANSWER: Focus on the required date of clearance. If the study cannot realistically be initiated for another 10 months, the date for the IND filing should be moved close to the date of study initiation. This will give more time for the IND to be refined and checked before filing. It is much better to take more time to work on the IND and then have a cleared IND, than to rush to file a poorly prepared IND which is placed on clinical hold.  

MISTAKE NUMBER 2: Companies often fail to develop a Product Profile for the NCE that is being developed.  

A Product Profile is the document which provides a clear rationale for the development. It also clearly lays out the Go/No-go decision points for the development. A development which is not guided by a Product Profile is an aimless development, and has a reduced chance of ultimate success.  

ANSWER: Every development should have a Product Profile. The Product Profile should be developed by the Project Team. Marketing are a very important contributor to this document. If the company does not have experienced marketeers, an expert marketing consultant should be hired to help to develop the Product Profile with regulatory affairs. The Project Team should then review and agree the Product Profile with senior management.  

MISTAKE NUMBER 3: Companies often start out working on an IND without spending any time on the development of a regulatory strategy.  

Next to the Product Profile, this is the most important document. The Regulatory Strategy document will identify the regulatory hurdles that exist for the product development. It will also identify the ways to mitigate the hurdles as development progresses. This is a dynamic document and should be updated yearly as the development progresses.  

ANSWER: Time should be spent defining the strategy for developing the NCE.  This should ideally be a global strategy.    

MISTAKE NUMBER 4: Companies often fail to tell the story of the development of the New Chemical Entity in the IND.  

The reviewer will find it difficult to understand why the NCE is being developed, or how it will eventually be beneficial to the patients.   

ANSWER: Every IND should have a cohesive story that is worked through the IND from the beginning to the end.  

MISTAKE NUMBER 5: The Chemistry Manufacturing Controls (CMC) section of the IND is often very poorly written and incomplete.  

Companies often submit a very poorly compiled Chemistry Manufacturing Controls section. This section is very critical and impacts upon the safety and quality of the material that will be administered to research subjects. It is one of the most complicated sections to write well, and yet with a proper regulatory strategy, is not difficult to do well.  

Some important points to cover in the CMC section of the IND are:

- Manufacturing of the NCE

- Manufacturing of the drug product

- Release of the NCE and the drug product

- Impurities that are present in different batches

- Qualification of the impurities in the toxicological batches

- clearly show which batches were used in which tox studies

- Analytical method development and validation

- Certificates of analysis for NCE and drug product

- Stability studies for NCE and drug product  

ANSWER: The CMC section must be a comprehensive and well written.   

MISTAKE NUMBER 6: Companies fail to include a comprehensive review of the Previous Human Use for the drug.  

Companies will often say that this is an NCE and it has therefore not been used in patients or research subjects before.

The excipients to be used in the formulation should be described as well as any information regarding their safety. If the NCE has been registered in other countries or studied in other countries, these data should be submitted, together with information on the excipients.  

ANSWER:  The Previous Human Use section should include information on the NCE if it has been studied in other countries, or if it has been studied in other indications. The information on dosing and the relation to adverse events can be very helpful to reviewers, and to the design of the clinical protocol.  

MISTAKE NUMBER 7: The IND is compiled very poorly and in a slip-shod way.  

The IND compilation process is a time consuming one. It requires a large team of people to write the IND, but a relatively small team of people to compile and QC it. The person charged with compiling the IND must be detail-oriented and have a sense of excellence about the final product.   It seems obvious that INDs should be compiled with detailed contents pages, every page should be numbered, etc.

ANSWER: The IND should be compiled and finalized by someone who understands what they are doing. They need to understand the drug development program, and be able to put themselves in the place of the reviewer.  

MISTAKE NUMBER 8: The IND that is submitted has not gone through a thorough process of Quality Control.  

An IND has a lot of data within it. As a result it will contain a lot of opportunity for inconsistencies. The process of compilation must allow sufficient time for a very detailed review and QC. A review which does not find any errors and mistakes is not thorough enough.  When a company hires one company to prepare the IND, there is no harm in bringing on a separate group to conduct the final QC review.  

ANSWER: A thorough QC must be conducted on the IND before it is submitted. All errors, inconsistencies and mistakes must be addressed before it is submitted to the FDA.  

MISTAKE NUMBER 9: Insufficient attention is given to the safety of the research subjects  

The IND will be placed on clinical hold if the safety of the research subjects are compromised by the study design, the quality of the material to be administered to them, or the toxicological evaluation that has been conducted. As the IND is compiled, very careful attention must be paid to how the study can be made safer for the research subjects that will take part in the study. This may mean that the study takes much longer to complete due to extended gaps between patients. Research subject safety will be paramount in the reviewer's mind. Paying attention to this will improve the chances of the IND being cleared.  

ANSWER: When the IND is prepared, emphasis must be given to the safety of the research subjects.  

MISTAKE NUMBER 10: The IND is written by many different writers, making it difficult to read.  \

If a good writer does not tidy up and harmonize these writing styles, the IND will be difficult to read. The reviewer should have an enjoyable experience as they read through the IND. This can only be achieved if a good writer harmonizes the writing styles into one standardized style.

ANSWER: The IND should be written in one harmonized style. =================================================================================================

These are only ten of the issues that Companies and sponsors should focus on to improve the chances that the IND will be cleared. The pointers on writing and preparing the IND also apply to European Clinical Trial Applications (CTAs), and clinical trial applications which will be submitted in other countries.

 Some Considerations To be Borne in Mind For the 505(b)(2) Application Route

The 505(b)(2) route of application is often seen by small pharmaceutical companies as a potential fast route to commercialization. The usual intention is to find a drug that is already off patent, find a new formulation, patent it, and then submit what is effectively an Abbreviated New Drug Application (ANDA). Is this all there is to it? There are many considerations to this strategy that CEOs need to be aware of. Three of them are outlined below. orna

A 505(b)(2) development is a development which is carried out when an established medicine is being developed for a different indication to that for which it was originally developed. This route can be used for medicines which are considered established. In other words, the safety and effectiveness of the medicine has been proved by many years of use. The medicine has a good safety margin and is not at risk for abuse, etc. The 505(b)(2) route allows companies to ask FDA to refer to the data on file for the medicine. This information was filed by the originator. If the application is successful, the idea is that new indications can be developed without unnecessarily repeating toxicology and clinical studies already carried out by the originator.  However, there are some considerations to be borne in mind nevertheless.

CONSIDERATION 1: The company that intends to develop a drug by the 505(b)(2) route must think through very carefully how the medicine will be commercialized. If the medicine is off patent, unless there is a way to patent a new development or formulation, the newly created medicine will effectively be a generic and there may not be enough incentive to spend resources on the development.

CONSIDERATION 2: A 505(b)(2) development may require that the studies that were not carried out for the originator are carried out for the new development. For instance, many established medicines that were developed in the 1960s, and the 1970s were not evaluated to the standards that are now required. Mutagenicity, carcinogenicity and reproductive toxicology studies may not have been carried out. The FDA may require that these studies are carried out for the new medicine even under the 505(b)(2) development to determine the risk benefit profile according to today's standards.

CONSIDERATION 3: Clinical development program must be designed and carried out for the indication for which the medicine is being developed. It will not be sufficient for a 505(b)(2) to conduct a bioequivalence study in a few healthy volunteer subjects.

PLs experience with many therapeutic areas including oncology, diabetes, anti-infectives, and pulmonary.

Dr. Speid began her career as a pharmacist in the UK, after which she completed a Ph.D. at the Centre for Medicines Research International, into the Safety Assessment of Medicines, Pre and Post Marketing. She has worked for large as well as small pharma companies, including Sanofi Winthrop in the UK (now Sanofi-Aventis), Ciba Geigy and Novartis in Switzerland (at Headquarters).  Small companies that she has worked for include Valentis, Inc. (Director of Regulatory Affairs), NewBiotics (Vice President Regulatory Affairs and Project Management), and Avera, Inc. (Vice President of Regulatory Affairs). Dr. Speid was an officer at the last two companies.  She has a Bachelor of Pharmacy degree from the University of London, UK (Kings College), and a Ph.D. from the University of Wales, College Cardiff, UK

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