47

Business Partners and Exchange of Safety Data

Development costs for a new chemical entity from creation to marketing range from $400 million to $2 billion (depending on how one calculates these costs) (see Frank, J Health Econ. 2003;325:330; Web Resources 47-1 and 47-2). In addition, patents are now being challenged and generics are proliferating. One response to these phenomena includes the development and marketing of a product by multiple partner companies. No matter which side of the argument one is on regarding the appropriateness of some drug development, these costs and risks are high and companies look for ways to protect themselves from the risks of failure.

One response is partnerships. The goal is to speed up development, share costs and risks, and use the additive or synergistic strengths of each partner. Codevelopment often is limited to two partners, but combinations of three or more partners are common, especially when expanding into areas (e.g., Japan, China) where language, laws, and customs are often a challenge for U.S. and European Union companies or small start-ups. The current trend in the pharmaceutical world is for codevelopment and copromotion/marketing of products as expenses skyrocket and simultaneous rather than sequential international development occurs. We are now seeing large, small, and midsized companies creating contractual arrangements with one or multiple other pharmaceutical companies, contract research organizations (CROs), and other vendors to handle development, sales, marketing, safety handling, regulatory matters, phone centers, manufacturing, and just about every other possible function except senior management. These contracts may be short-term or longterm and involve companies all over the world.

Whenever two or more companies join forces for whatever reason, a written contract must be developed between or among them. Normally, these contracts are developed by the “business development” or “licensing group” with input from the legal department and other groups on a “need-to-know” basis. Often they are developed under great secrecy (for competitive reasons), and others in the company are not informed of the situation until the last minute, when their input and/or approval is requested, often with a minimal amount of lead time. (“The CEO wants to sign this contract tomorrow morning. Please approve your section now.”)

The safety group (unless involved in due diligence) may be one of those groups learning about the agreement at the last minute and asked to review a document with a minimal or even nonexistent safety section. Sometimes when the safety section is present, it is incorrect and would not keep the company in compliance with regulations in countries where the partners are working or help protect the company from litigation and other pitfalls.

When such a situation occurs, the immediate acute step is to ask that the safety section, if inadequate, be removed and replaced with one or both of the following:

1. A “generic” or “one-size-fits-all” safety section (see below).
   
2. A statement that a safety section is needed and will be developed by the safety groups of the respective signatory companies to cover safety data issues within, say, 90 days. It will be appended to the agreement or will act as a stand-alone agreement (whichever the lawyers prefer). This time frame may need to be shortened if the sales or studies start in a shorter time. Often, however, studies or sales will not begin for several months, giving all parties sufficient time to develop a safety section.

There are multiple reasons to have safety agreements:

• To remain in compliance with health authority requirements (e.g., FDA: 21CFR314.80(b); EU: Volume 9A Sections 1.3 and 2.2.3.e)
  
• To give guidance and instructions to all involved parties with regard to their responsibilities for drug safety
  
• To ensure that all parties receive the safety documents they need to remain in full compliance with all regulatory and legal requirements in their jurisdictions of sale or study
  
• To ensure that adequate signaling is done and that a benefit-to-risk analysis incorporates as complete a database as possible
  
• To produce the best product labeling possible to protect the public health
  
• To have data ready for a corporate audit or health authority inspection
  
• To have data available for litigation should that situation arise

The safety department should be informed of any agreement being negotiated early on in the process so it can review the document and determine what is needed concerning safety. This should be included in all company standard operating procedures (SOPs) on the negotiation of agreements with other parties where drug products (either finished products or components) are involved. Agreements for non-product-related items do not need to be included (e.g., raw chemical products, supplying vending machines, or ordering furniture).

Many types of arrangements must have safety agreements. They include but are not limited to agreements on licensing-in or licensing-out; manufacturing; comarketing; codevelopment, including preclinical or clinical development; advertising; clinical study research; consultants; contract sales forces; distribution; disease management programs; patient support programs; promotion and copromotion; speakers bureau consultants; master vendors; other vendors; and other services. These contracts may cover all possible permutations: prescription drugs, over-the-counter drugs, drugs that are prescription in one country and over the counter in another, biologics, blood products, devices, nutraceuticals, cosmetics, foods, and combination products (a device with a drug in it, such as a prefilled syringe, a drug-impregnated gauze pad, or two drugs in one tablet).

Even before any agreement is on the table, the drug safety and the legal groups (at least) should develop a “boilerplate,” “generic,” or template agreement approved by management and general enough to be inserted into almost any type of contract anywhere in the world, either in the body of the contract or as an appendix, until a customized agreement is made to replace it. Multiple regional versions and languages might be necessary. The agreement should, at the very least, specify the following:

• Exchange between the parties of all serious adverse events (SAEs) from clinical trials, spontaneous reporting, solicited reporting, literature, special arrangements (e.g., named patient or compassionate use) and health authorities. Cases should be exchanged as either MedWatch/CIOMS I forms or E2B files within a specified time frame from first receipt by anyone in the companies or their agents. They should be exchanged in sufficient time to meet expedited reporting rules (usually 15 calendar days) so that exchange should, in general, be no later than 10 or so calendar days. Deaths and lifethreatening SAEs from trials should be exchanged in time to meet 7-day reporting requirements (e.g., 5 calendar days) for deaths and life-threatening events. If this is too difficult to distinguish from other SAEs, then all SAEs should be exchanged in 5 or so calendar days.
  
• All regulatory submissions (Periodic Safety Update Reports [PSURs], NDA Periodic Reports, Annual Reports, and their local equivalents) should be exchanged between the parties within a specified time (e.g., 1 week) after submission to the health authorities.
  
• A formal and detailed safety agreement will be completed by the two drug safety groups within, say, 90 days of the signing of the contract.

The above generic agreement should suffice in almost all cases until the formal safety document is created. Additions, of course, may be added to the generic agreement if the specific case warrants it and if there is sufficient time to get agreement internally and from the other contractual partner. This could include exchange of communications with the health authorities, including safety reviews of PSURs, literature searches, and a data dump (e.g., a paper printout or an electronic file of all AEs in the safety database) from the partner holding the safety database.

As soon as the type of contract is determined and the safety department is brought into the discussions, the area of involvement should be ascertained: geographic territories (e.g., United States only, United States and the European Union, Canada, Poland, etc.), regulatory and marketing status indications (MA/NDA approved, in clinical trials only), labeling, etc. This allows the tailoring of the specific agreement to ensure that all needs are met.

At this point the safety and regulatory departments will be able to determine what is needed. If the drug has never been marketed, for example, there will not be an issue of postmarketing spontaneous SAE reports, and this may not need to be included in the agreement (though a clause indicating that the agreement will be revised, say, 60 days before a marketing request is submitted anywhere in the world does). If more than one other partner is involved, this also allows the signatories to determine various responsibilities and negotiate any new or altered requirements.

Again, there is no “one-size-fits-all” safety arrangement that can simply be dropped into a contract to take care of everything. Each agreement must be negotiated individually. Usually, face-to-face contacts between the two (or more) safety departments facilitate the successful preparation of a safety agreement. As always, contrary to the saying, business is personal, and it is always easier to develop a successful working relationship of trust and confidence if personal contact has been established rather than relying only on e-mails, video conferences, and telephone calls. A meeting should be set up at the earliest reasonable time after preliminary negotiations are started to hammer out the final document. The safety department needs to be given sufficient authority to negotiate such an agreement (pending, of course, final management and legal approval on both sides). The complexity of these agreements increases exponentially if multiple companies and CROs are involved. In such situations, it is usually worthwhile for one of the companies or partners to take the lead in safety matters.

For companies that make many agreements worldwide, it is imperative that a database containing the key points of the safety agreements (and if possible the imaged agreements themselves) be maintained. Multinational companies may have tens of thousands of such agreements, in multiple countries, in multiple languages, often with differing products, durations, responsibilities, and territories. The agreements will become out of date rapidly as new terms are made, new products launched, new formulations made, and new partners (or distributors or sales forces, etc.) brought in or terminated. A database will help track this. The database may start as a spreadsheet, but it may be necessary to develop (with the IT department) or purchase a database to track and report on agreements. As always, the database must have the appropriate security, testing, validation, and change control.

Historically, the legal and new business departments will not keep sufficiently detailed records to ensure regulatory compliance regarding safety matters (a sad fact). Thus, it falls on the drug safety department to do its best to ensure that all revisions to agreements are transmitted to the central (or designated) safety department. A dedicated person must be designated and have the responsibility to track and revise such agreements and changes to them. Any new conditions (new INDs, NDAs, Marketing Authorizations, new products, new regulations, new PSUR dates, etc.) must be transmitted to the drug safety groups involved (e.g., the processing group, the PSUR group). In the European Union, the QPPV is responsible for ensuring that this occurs. Periodic reports of contracts in force, dates of expiration (where they exist), and obligations should be issued to the parties who need them.

Stay updated, free articles. Join our Telegram channel

Join