By Zachary Shapiro
Hello from the Post-Trial Responsibilities conference! I will be live blogging session 2: where speakers will be providing important perspectives on PTA. Barbra Bierer is monitoring the discussion.
We started with Richard Klein calling in from FDA:
Richard is talking about post-trial responsibilities. He points out that there is a justice issue here with ensuring access to health care and up to date interventions. He points out that while the FDA can encourage Post-Trial Access (PTA), it has no authority to require or ensure it. He points to moral authority, rather than legal. Foreign trials, however, are a different story, as the FDA has sway over protocol applications that are submitted in the US. Richard begins highlighting some specific considerations for protocol drafters and IRBs: particularly focusing on determining monitoring plans, as well as figuring out financial responsibilities for the provision of PTA.
He moves on to highlight that there is more of a moral obligation than a legal obligation. FDA is supportive of the provision of PTA. He believes that enthusiasm must be tempered, as there are situations when PTA is not appropriate. These include studies that have significant safety concerns, studies of bio-markers as well as validation studies that do not specifically examine safety and effectiveness. There are also situations where PTA is simply not feasible, particularly if additional drugs do not exist (one thinks of the recent Ebola treatment), if there is insufficient safety data, or if there is no practical capacity or resources to provide safety monitoring. We must also be aware of financial limitations, especially for start-up biotech firms that might not have deep pockets.
He ends by dispelling a few common myths that are seen as delaying PTA. Richard argues that the application process is not burdensome or too time consuming, nor is it too complicated. He also points out that the FDA approves the vast majority of requests for expanded access to study drugs.
Daniel Wang, from the London School of Economics (where your humble blogger received his MSc)
Daniel points out that in the case of Brazil, he is not really sure that they are following the exact words of the Declaration of Helsinki. He goes through the unique case of Brazil, highlighting that PTA in Brazil is influenced greatly by the Brazilian federal constitution .
Daniel methodically went through several important court cases that have set the scene for PTA in Brazil. He highlights that these decisions have caused a legal battle in Brazil, with the government and sponsors fighting over which group should foot the bill for the provision of PTA. This has led to “passing the parcel” in his view, with patients suffering the consequences of groups trying to blame each other, rather than work towards real solutions.
Daniel ends by highlighting that in Brazil, paradoxically, too many legal protections could actually be harming patients. He warns that the situation as it is could cause a research drain out of Brazil, with sponsors preferring to go to countries where PTA is less likely to be enforced. While he has not seen data to this effect yet, it is something to be aware of.
Jocelyn Ulrich, from PHRMA:
Jocelyn starts with a reminder that not all drugs tested end with approval. Furthermore, the cost of approval can be very expensive, meaning sponsors have to make difficult decisions about which drugs to provide. She highlights that PTA is a pressing, timely issue, especially with the expansion of multi-regional clinical trials, making discussions like this very important.
Jocelyn goes on to discuss what a sponsor’s current role is in providing PTA. She believes that any provision of PTA must be discussed and provided for in the clinical trial protocol. Also, we must remember that there are circumstances where the sponsor may find that the risk is too great, or decides to halt production of the drug, and that such decisions have an impact on whether or not they can provide PTA. The most important thing, however, is that the sponsor be open and communicative if any changes have to be made to any commitment to provide PTA.
Ramadhani Noor is up next, and will provide an investigator’s perspective on PTA:
Ramadhani says that investigators need guidance about PTA, as they cannot make provisions on their own for such a complicated and potentially extensive operation. He highlights that PTA cannot be provided in a vacuum, and must coincide with appropriate changes and buttresses to local healthcare systems, as well as improvements in the standard of care. He agrees that provisions must be made early, and detailed in the clinical trial protocol.
He thinks that the guidelines have not taken an active enough role in addressing PTA. Because of this, investigators have had to take action to support PTA, interfacing with local health officials. He says the problem is particularly striking in countries with less developed infrastructure, pointing out that, for example, PTA in Africa faces different questions than PTA in other settings. This issue is not just one of funds, but rather that there is a lack of decision making frameworks. This makes it difficult to easily adopt and scale PTA programs. He reminds the audience that this is not simply an issue about PTA, but also an issue about data. He thinks that evidence to support plans for PTA must be generated in parallel with product development, so that PTA can be provided in a responsible and effective way.
Most importantly, it puts investigators in a difficult position if they have to fight for these provisions, which really should be decided beforehand by people who are responsible for actually providing PTA. Ramadhani argues that these provisions are really policy decisions, especially those related to introducing new “products” into markets. This makes it important to create new partnerships between investigators, sponsors, governments and global development agencies, so that the issues of PTA can be addressed properly.
Mitchell Warren, from AVAC, will close this session:
After offering a “disclaimer” that he has not participated in clinical trials himself, Mitchell begins by discussing AVAC, an AIDS Vaccine Advocacy organization. PTA is hugely important in combating HIV/AIDS, as management of this condition requires a life-long effort and commitment. Mitchell thinks an important facet of PTA involves the translation of a successful clinical trial into a long-term public health improvement.
He tells the story of an HIV prevention trial in 2004. Patients demanded life-long provision of ART therapy in the event that they became infected during the trial. In 2004 however, nobody was providing such PTA. There was also a question of who exactly was in the “community” of those who should be provided with PTA, as researchers wondered whether obligations extend to family members or significant others.
Mitchell continues by talking about the Guidelines for Good Pharmacoepidemiology Practices (GPP), and what these say about PTA. Crucially, he says that PTA, in his view, is really about defining expectations. He thinks it’s important to negotiate PTA upfront, and compromise, so that expectations can be met appropriately. This involves developing a clear strategy and funding mechanism for the provision of PTA.
He concludes by discussing what he calls “research to roll-out” and how PTA can be incorporated into the process of clinical trials. He looks at the experience of Oral PrEP in Peru, where there was clinical trial success, but it was not approved for marketing after the trial was over. This is not because of a lack of application by the sponsor, but because of a delay in the regulatory agency. Such situations complicate the provision of PTA, highlighting how difficult this issue really is.