Oct 22, 2014
Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert
One of the recent major trends in the pharma world is the joint development and marketing of drug products. This entails all sorts of agreements with other companies, both in the home market and abroad. We may now see several companies marketing the same drug in the US and other companies marketing the drug abroad. Clinical trials may be done jointly or they may be outsourced to CROs or other pharma partner companies.
All of this means that large amounts of data are being gathered and exchanged between companies. In the world of drug safety and pharmacovigilance, there are particular requirements for the exchange, databasing, analysis and reporting of safety data.
To this end companies must establish written agreements with all parties, companies, individuals, investigators, CROs, patient support organizations, poison control centers (if they are being used to collect AEs), telephone call centers and any other business partner that might get safety data that a company needs. This also includes all companies listed in the labeling such as distributors, manufacturers, partners, etc. These agreements are known as “safety data exchange agreements” (SDEAs). They will be asked for and reviewed during inspections by FDA and other health agencies.
What Should be in the Safety Data Exchange Agreements?
At the very least, the SDEA should allow for rapid exchange of all serious adverse events (SAEs) for determination of whether expedited reporting is necessary. This applies to both clinical trial and post-marketing situations as well as any special programs such as patient support programs. Some companies want just MedWatch or CIOMS I forms for each case; others want the source documents also.
All SAEs should be exchanged in less than 15 calendar days to allow an expedited report to be submitted within the 15 day requirement in most jurisdictions.
Deaths and life-threatening SAEs should be exchanged in less than 7 calendar days.
Non-serious AEs should be exchanged as appropriate. In clinical trials this may be only at the end of the study (though some companies want them more frequently for signaling). For marketed products, particularly if some non-serious cases must be submitted within 90 days in the EU, this may be monthly or even more frequently.
All follow-up data must also be exchanged.
Aggregate reports (Annual Safety Reports, DSURs, PSURs/PBRERs, PADERs, etc.) should also be exchanged usually within a week or so of their completion or submission. Timing should be a function of the regulatory reporting requirements.
Other: Some companies exchange signals, regulatory correspondence in regard to safety matters, IRB/EC safety comments and requirements, Data Monitoring Committee findings, market withdrawals for safety issues, new health authority decisions or requirements, preclinical safety issues etc.
The agreements should have some provision to ensure that the provisions in the document are really being done correctly. This could be periodic audits, reconciliations, meetings or teleconferences etc.
There is often pushback from business partners when these clauses are proposed in a contract (“Our job is to sell your drugs, not talk about side effects.”), particularly from companies in countries where safety reporting is not done or is not a priority.
Who Sets up the Agreements?
Since the SDEA is a written agreement which is binding between the partners, the Legal Department should review and approve the document. Sometimes it is included in a master (services) contract or agreement. Sometimes it is handled as a separate document between the drug safety groups. Sometimes the master contract has a brief boilerplate section (see below).
Issues often arise here as these company-to-company agreements are set up by research, sales or business development groups whose main goal is to get studies going or sell more drug. Drug safety (side effect reporting) is rarely high on their list of priorities. In fact, often they don’t even think of it at all or they realize, at the very last minute, that they need a safety section. I have often been in the difficult spot of receiving an email or agreement with the note that the CEO will be signing this tomorrow and “Is the safety section OK” or “Please send us a safety section immediately”.
Even worse is when the agreement is signed and the safety department is not informed about the new partner or new drug. I remember receiving an SAE for a product none of us in the safety group were aware of. We presumed it was mistakenly sent to our company and we started to hunt down the NDA/MA holder to forward the case to them. We were stunned to find out that we were the NDA/MA holder and had been for some months. Nobody told us and, of course, the case was ours.
The key players in setting up SDEAs are the lawyers. All contracts are (or certainly should be) approved by the Legal Department. In small companies these issues are usually not a problem as the staff all knows each other and cooperates well. In larger companies with lawyers sitting in offices on two or more continents and with many attorneys handling different matters it may be hard to identify the person handling drug safety matters.
Sometimes the contracts are not in English and sometimes they do not specify which products are involved but rather indicate that the sales groups will decide every 3 or 6 months which products will be sold, imported, exported, studied etc.
The other key groups involved in SDEAs are the business development people. Again in small companies these individuals may be easily identified and educated on the PV and safety requirements for business deals. In large companies this can be harder, particularly if the general manager or head of each subsidiary has the power to make deals without necessarily telling the home office. Frequently, these types of agreements fall through the cracks.
What is the Role of the Legal Department?
The Legal Department is the natural ally of drug safety for SDEAs. It is in the company’s interest, of course, to remain in compliance with the laws and regulations in all markets and the Legal Department is there to help ensure this. Although many attorneys are not familiar with the regulatory requirements for safety reporting, in my experience they are happy to help the DS group get the appropriate wording into the contracts, assist in SDEA preparation and “wordsmith” the documents to be sure they are clear and cover the points necessary.
In many companies, the Legal Department knows all of the partners involved in the marketing of the companies’ products. In large companies selling hundreds of drugs in over a hundred countries there may be tens of thousands of such contracts! This was certainly the case in one of the large companies where I worked for many years. We had over 10,000 contracts in some 110 countries around the world. There may or may not be a database with them. They may reside in multiple locations around the world and many are not in English. The Legal Departments, in my experience, are happy to help Drug Safety with the SDEAs but often do not themselves know about all the contracts in place around the world. Sometimes the Finance Department is best informed about all the agreements around the world as they have to send and receive money!
Is there an SDEA Boilerplate or Template?
It is a wise idea to develop one or several boilerplates that can be inserted into all contracts and agreements. They should be developed with the Legal Department and agreement gotten from the Business Development Group so that these are automatically added to all contracts. This is not at all unusual as most contracts have multiple clauses that are “boilerplates” covering other matters such as insurance, liability etc.
The boilerplate should include a brief paragraph indicating why the section is present (to protect the public health and to adhere to all regulatory and legal safety reporting requirements), what gets exchanged (see above: CIOMS I forms for SAEs, source documents etc.), when they are exchanged, aggregate reports, emergency situations (tampering, market withdrawals, study stops etc.).
Usually this boilerplate is not sufficient to cover all matters and a sentence should be added indicating that the parties will put in place a formal, detailed, written SDEA within xx days of the signing of the contract. The “xx” depends on when patients will be exposed to the product. Some mechanism for safety exchange must be in place before any patient receives drug.
What are the Operational Mechanics Involved?
There is no “one size fits all” SDEA, though usually they are similar. Actually this is the rub. For large companies each agreement may represent a “one off” where there are small but real differences amongst the agreements. For example, you may have to send source documents to company A by day 3 and CIOMS I by day 8; for company B by day 2 and day 10 respectively; for company C MedWatchs for US cases and CIOMS I for ex-US cases on day 5 for SUSARs and day 8 for all other SAEs etc. In other words, each is sufficiently different to force different procedures for each partner. In large companies receiving upwards of 100,000 or more AEs/SAEs a year and with dozens to hundreds of partners this poses major operational issues.
The DS/PV team should continuously educate the rest of the company that SDEAs must be in place to protect both the company and the public health. There must be a written SOP or procedural document in place signed off at the highest level obliging all departments that might see safety issues to have mechanisms in place for SDEAs and the receipt and handling of safety matters.
Many companies have one or more individuals dedicated to preparing, tracking and enforcing SDEAs.
There should be a database maintained for all SDEAs for all products listing partners, dates of the agreements, drugs covered, obligations and documents exchanged, etc.
There must be tracking of those companies who violate the agreements by sending late reports or by not sending reports at all. How one can know that a company far away is not sending SAEs is another tricky issue entirely and involves working with the corporate quality and auditing groups.
For a somewhat more detailed discussion of Safety Data Exchange Agreements, see Chapter 47 in my book: Cobert’s Manual of Drug Safety and Pharmacovigilance 2nd edition.
In summary then, companies must have safety exchange agreements in place in order to remain in full regulatory compliance.
Tags: drug safety, Pharmacovigilance, sdea