By Sara Gambrill
On Dec. 1, 2011 in Cambridge, MA, law firm Pepper Hamilton’s Timothy Atkins, partner, life sciences, and Jason Reiser, associate, life sciences, gave a presentation as part of the firm’s Life Sciences Speaker Series. “Clinical Trial Contracting: Lessons Learned” is the second in the series.
Throughout their talk, Atkins and Reiser shared best practices for how the biopharma industry could be most effective in contracting clinical trials, from the legal perspective — with a particular focus on multinational Phase 3 clinical trials. The two main takeaways for sponsors were: Think ahead, and involve your counsel early on. They also emphasized the need to select a good CRO to help run very large clinical trials.
Though many different constituencies contribute to the successful conduct of a clinical trial, the presenters focused mainly on the contracting process with investigative sites. “Contracting with clinical sites is probably the biggest rate-limiting step that sponsors have in operationalizing trials,” Atkins said.
Identify The Team
For a Phase 3 clinical trial to run efficiently, Reiser described the need to start on the right foot. He believes it essential to have a kickoff meeting to meet the internal team working on the trial, including the chief medical officer, some of the scientists, perhaps members of the regulatory team, and others, as well as the external team — the CROs — if not in person, then over the telephone during this meeting.
As legal counsel, Reiser wants to learn: What is the drug supposed to do? What are the anticipated outcomes? What are some of the possible downfalls? How many CROs are involved? In which countries is the study being conducted?
“I want to sit down for a couple of hours and get a good sense of things, so when the first contract comes in, I already have a great knowledge base to help run the trial,” Reiser said. Meeting face-to-face is important for building rapport before the work begins so the first conversation between the company and its counsel isn’t about a problem. The kickoff meeting is also a good time to point out potential issues to each other that neither side might have thought of. “The more comfort you have with your team — the more familiarity — the better it will speed the process along later on, especially when things get hairy,” Reiser said.
Atkins stated that an all-one-team approach to doing the trial is critical, instead of approaching the trial as separate teams of clinical and legal. Having a client services team at the law firm dedicated to the trial is also important. “If you’re dealing every day with the same people at the law firm who know what the trial is about, then they’ve gone through the issues, they know what needs to be negotiated and what your ‘gives’ are and what you’re not willing to do. That familiarity is critically important from a legal perspective. Your team should certainly have contracting experience and also regulatory and international experience,” Atkins said.
Roles and responsibilities should also be clearly delineated and assigned. There can be overlapping areas, so it’s important that the legal team know what each party is supposed to be doing and that everyone is well-coordinated, working together, and interacting regularly.
Identify And Prepare All Legal Documents To Be Regularly Used In Clinical Trials
Atkins and Reiser recommend identifying the necessary legal documents for a trial and having them in place early on to have a smooth contracting process. These documents can include the non-disclosure agreement (NDA), clinical trial agreement (CTA), letter of indemnity, and various vendor contracts.
NDAs are typically written up first. Though fairly straightforward, sponsors need to keep a few considerations in mind when having them made up. “NDAs are considered dime-a-dozen type agreements, but they’re there for a reason — to protect proprietary confidential information. It’s a good idea to tailor it to what you’re trying to accomplish. One-size-fits-all isn’t the best approach for suits or for NDAs. You need to think about what you’re trying to protect, how long you need to protect it, and the things you’ll give on,” Reiser said.
Sometimes sites, notably academic institutions, have their own NDAs that they will hand back to the sponsor to use instead. Sponsors need to be prepared for this situation, deciding whether they will respectfully insist on their own form being used or, if the language is different but says the same thing, are prepared to give. It’s also important to think of all the different vendors a sponsor will need contracts for and have them in place or know that the CRO will take care of some or all of them.
The CTA “comes in many flavors,” depending on the scope of a clinical trial and how many countries the research is conducted in. A CTA can be a two-, three-, even four-party agreement. It’s important for sponsors to anticipate some of the contract scenarios they might encounter outside the United States. For example, though a sponsor may have a CTA with an investigator who is going to conduct research for the trial at a hospital, the hospital may not be a signatory to the CTA. In this case, it may want the sponsor to sign a letter of indemnity so that if anything goes wrong, the sponsor will pay for the damages. Reiser believes that it’s fine for sponsors to sign this letter of indemnity, but that they should ask for something in return, such as a signed consent from the hospital that the sponsor had permission to conduct the study there in the first place. “It’s important to think about your paper trail. What are you going to point to if something goes wrong and somebody asks, ‘Did you have permission to conduct the study at the hospital?’ A couple of sentences should take care of it.”
Sponsors in this situation might also want to get confidentiality agreements, as the PI (principal investigator) will be using staff at the hospital. Atkins pointed out that one of the issues in this scenario is that the institution is not signing the contract, but the PI is, though the PI will be using the personnel of the institution. “There is a property issue here. You have to think about how you’re going to get a release of claims from the institution as it relates to the use of their personnel for extracting data and putting them on a case report form and the like.” Being ready with one’s own documents to be signed when the institution asks for a letter of indemnity is key to saving time.
Legal Review Of Both Informed Consent And Protocol
Atkins and Reiser recommend that sponsors have their law firms review the protocol — early on, before FDA approval — and the informed consent side by side to ensure consistency between the two documents and regulatory compliance. For example, safety reporting and medical care should be described clearly in both documents and in a consistent manner. “We don’t think many sponsors actually have their legal departments look at the protocol and read it through, compare it to the informed consent, and ask, ‘How are these things different?’” Atkins said.
Counsel can also advise on anticipated developments arising from recent lawsuits and regulatory action and guard against “failsafe trials,” or trials set up to find a certain answer, by reviewing the protocol for risk avoidance. Atkins said, “It may not be at all what you’re trying to do. We know how to read through a protocol and say, ‘That’s a risk. You should probably get another endpoint or something else in there to take away that risk.’”
Every informed consent document goes through a site’s IRB (institutional review board), and the IRB may require changes to it. This presents legal risks when a sponsor must decide what to do from there. Reiser said, “It could be a material change, and, if you made it for one site but not all your other sites, you’ve just set yourself up for a real problem, in terms of litigation around informed consent.”
Sponsors also should provide counsel with a list of prospective sites. “We want to know who your sites are as early as possible so we can run it through our conflict-checking process, and we can then either start getting conflicts waived or we can tell you which ones are going to be a problem,” Atkins said.
Establish Tracking Mechanism For Contract Review Process
Figuring out what the sponsor’s gives are, what language the sponsor will and won’t work with, and what types of issues the sponsor does and doesn’t need to go to legal for are important to establishing a tracking mechanism for the contract review process. “It’s important for us to keep the trial moving. We all want to know where every contract with every site is. Who has the ball? How long has it been there?” Atkins said. CROs tend to run the process, but the law firm should be able to, and, either way, someone needs to be accountable for tracking the process and allowing everyone on the team to see on a weekly basis where all the contracts are.
If the process isn’t thought through and led by someone, “a contract can circle the globe in three weeks, and you’re back where you started,” Reiser said. “Have a spreadsheet, have a process, and have team leaders who are in charge, so, if a contract’s missing, you can track it. You don’t want it sitting in limbo.”
Identify The Geographic Footprint Of The Trial
Biopharm companies running a multinational, multiyear Phase 3 trial face complexities that revolve around the many different countries where the research will be conducted. Contracts drawn up for clinical research conducted in the United States have to be made appropriate for use in foreign jurisdictions, which will involve translation but also could require breaking the contract apart into several pieces.
Atkins advised, “You want to keep the contract as consistent as you can across jurisdictions. You must have the explicit intention when you break those contracts apart and make them appropriate for the foreign jurisdiction that you’re not losing something in the translation, that you have consistency across your contracts and across your trial. It puts a premium on your organization’s communication skills.”
It may seem obvious that biopharma working internationally would need international counsels, but the form they might take is not as obvious. Big Pharma with offices and legal teams in all the countries where their research will be conducted has to make sure they get the legal input they need. Other companies may choose a big law firm with international offices or a U.S. law firm that has a network of firms — international affiliates — it works with. Reiser said, “Whatever you do, you need to know one thing: Regardless of how big, how broad, how well-known the counsel is, they have people on the ground in the countries where you’re going to do clinical trials. When you’re vetting law firms, know what capabilities they have and where.”
Reiser says it’s key to have one lead counsel to vet all the counsel, make sure the process is running efficiently, and that all the necessary calls are made. “Law firms need to have been through the process, know the players involved, get you through the Ministry of Health, know how many ‘gold seals and red ribbons’ you need on documents, and identify contract issues you simply hadn’t thought of,” he said. What is necessary for each document needs to be understood ahead and built into the process.
The same applies to a company’s choice of insurance firm. Biopharma companies should work with insurers that have done work for international clinical trials before. “Ask them: ‘Have you been in this country before? Is this the first time you’re going to be writing a policy for clinical trial coverage in this country?’” Atkins explained.
Before conducting clinical research in the EU, biopharma companies must have a legal representative, the sole purpose of which is to grant the EU jurisdiction over the company. It gives the EU authority to contact the company and communicate with it. CROs often offer this service to smaller companies.
Clinical Trial Agreement Terms
Atkins and Reiser ended their talk by discussing some of the areas of the CTA that sponsors should pay particular attention to. One of the major areas of consideration is compensation. They advised sponsors to make compensation attractive to sites so that their trials get attention throughout the trial but also ensure that start-up fees are recoverable under certain circumstances, such as when a site never enrolls a patient or hasn’t enrolled one for six months. They also recommended that compensation be structured so that sites don’t get fully paid until they fully perform.
They reviewed their recommendations to sponsors to think through what they wanted in terms of IP, confidentiality, and indemnity. They also stressed the importance of including the timing of publication in the CTA and to be consistent about it across contracts.
One of the issues that can come up in contracting work with foreign countries is the Foreign Corrupt Practices Act (FCPA). Atkins said, “The FCPA is a huge issue these days in terms of enforcement.” Because many foreign health systems are government-run, sponsor companies are actually contracting with a foreign government when conducting clinical research in countries outside the United States. “Make sure you’ve done all your due diligence on compliance around FCPA and that you’ve done fair market value studies on your payments to clinical research personnel and your fees. Make sure when you’re making an investigator payment that you’re not handing out gifts and things like that.”
Atkins pointed out that there’s very little litigation around CTAs; their purpose is to lay out normative behavior. CTAs describe expectations and provide sponsors with the ability to withhold payment if expectations are not met. Ultimately, he recommended that sponsors send investigative sites a “middle-of-the-road” contract. “Send a contract that’s easy for them to accept. You’re going to be better off doing that than going through multiple versions of a contract.”