Sidestep FDA Form 483—And The Resulting Setbacks

Bringing a new drug or medical device to market is incredibly exciting for any sponsor. Ideally, you’d like the clinical trial phase to proceed without delays, so you can get your new drug to market quickly—and start helping patients.

The FDA can issue a Form 483 after an inspection where an investigator has observed conditions or issues at a facility that might constitute violations of the Food Drug and Cosmetic Act and serves to alert the organization’s management. As a best practice, if issued a 483, companies or research centers should respond in writing without delay. The response should include a corrective action plan addressing the violations which the organization should immediately implement. Failure to respond or failing to take remedial measures could result a Warning Letter being issued by the FDA, or cause delays in studies and development.

The FDA maintains a list of Inspectional Observation Summaries broken down by program area (biologics, bioresearch monitoring, drugs, devices, etc.) which can be found on the FDA website. By viewing this data, sponsors, clinical sites, CROs and IRBs have the opportunity to learn the most common reasons for 483 and how to avoid similar pitfalls during the clinical trial process.

For example, in the program area of Bioresearch Monitoring, 248 Form 483s were issued between 10/1/2016 and 9/30/2017. Common reasons for the 483 include:

• An investigation was not conducted in accordance with the signed statement of investigator and/or investigational plan (frequency: 140 times)
• Failure to prepare or maintain adequate and/or accurate case histories with respect to observations and data pertinent to the investigation and/or informed consent (76 times)
• Informed consent was not properly documented in that the written informed consent used in the study was not approved by the IRB and/or was not signed by the subject or the subject’s legally authorized representative at the time of consent and/or was not dated by the subject or the subject’s legally authorized representative at the time of consent. (14 times)

Stick to the plan

An investigational plan forms a roadmap for any clinical trial, giving a brief overview of the type and scale of the study. Mandated by the FDA, it’s the outline that gets a trial from start to finish: quickly and safely. Sponsors and investigators must either stick to this plan, properly amend it—or risk receiving a Form 483.

An investigational plan is detailed and thorough, but a sponsor won’t typically be on site to ensure it’s being followed. As such, it’s important to know that your contracts and terms with your CROs are solid and equitable. Failing to review contracts could leave you open to both liability and FDA delays. Our attorneys possess the necessary industry experience and a meticulous, efficient approach to contract reviews which means sponsors can be confident that they’re protected should an investigational plan go awry.

Let the record show everything

To gain the best results from a trial and to pass inspections, meticulous record keeping is a must. Much like an investigational plan, proper record keeping requires diligence and thoroughness. It involves preparing and maintaining case histories and taking detailed documentation at every stage, from observation to delivery. Failing to properly monitor and maintain records for a trial isn’t just a common reason for a Form 483, but can also compromise the study.

Contracts Associates will ensure that each sponsor/CRO agreement includes detailed language about monitoring and record keeping. The agreement is intended to protect the sponsor in the event your CRO fails to keep proper records. Working with us will allow sponsors to harness our knowledge and expertise, which means you won’t have to worry about this type of exposure.

Obtain informed consent

The FDA doesn’t just monitor the safety of publicly available drugs or devices. It also monitors the safety of clinical trial participants, and obtaining informed consent is a core element of that.

Sponsors must ensure trial participants know their rights in relation to a clinical trial they’re considering. This includes exposure to unknown risks, possible side effects, and potential outcomes. Ensuring that your study is compliant with FDA regulations about informed consent is crucial to keeping your company protected and ensuring your milestones are met.

Your in-house counsel might not have the time or manpower to carefully review a trial’s informed consent forms before signing off on them. The attorneys at Contracts Associates can provide the additional assistance you need, on an as-needed basis. We can help you stay on schedule and ensure compliance with informed consent requirements. There’s no better plan than to have informed consent contracts reviewed quickly and thoroughly by experienced industry professionals like us.

Implications of Form 483

It’s important to keep in mind that Form 483 does not constitute the final Agency determination of whether cited conditions are absolute violations of the FD&C Act. Form 483 is a factor for consideration, along with all evidence or documentation collected on-site, and any responses made by the company. Only then does the FDA make a final determination as to what future actions might be necessary.

Proactive approaches with Contracts Associates

At Contracts Associates, we work with sponsors to ensure their clinical trials don’t fall behind schedule or expose the company to undue risk. We can even produce and maintain a personalized “risk register” for you, complete with contract terms and other matters that we become aware of in our reviews—helping you avoid future problems.

Our extensive industry experience means we don’t require training—or the time, cost, and effort associated with a learning curve. We provide quick and meticulous turn-arounds, and can help you meet your milestones. Contact us today to find out how we can help you.

More Clinical Trials in China in the Future?

The China Food and Drug Administration (CFDA), which became a regulatory member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in June 2017, is now moving forward with the implementation of several ICH guidelines in order to further the development of innovative drugs and devices in China, and align with global regulatory standards in manufacturing and development.

China’s implementation of the ICH guidelines will not only help ensure that global standards of quality and safety are met but can help reduce drag on pharmaceutical companies’ timelines by streamlining various processes such as clinical trial application and approval. Additional reforms will likely increase the number of Chinese hospitals and research centers able to manage clinical trials without having to undergo an extensive certification process.

These ICH-driven reforms will likely provide US pharmaceutical companies with greater opportunities to include China in global clinical research as well as greater access to the Chinese markets. As a member of ICH, China will be expected to continue implementing regulatory requirements for the manufacture and testing of study drug products. We expect to see an uptick in the conduct of clinical trials once the controls are in place to ensure that quality, safety, and efficiency is consistent across the Chinese markets.

We at Contracts Associates are looking forward to the further integration of China’s prominent researchers into our global clinical trials.

FDA suddenly adds four-letter meaningless suffixes to new biologics’ nonproprietary names

Back in 2015, the FDA implemented a policy which required the addition of suffixes to biosimilars. On June 1 2016, the FDA suggested that sponsors could provide the FDA with up to 10 preferred proposed suffixes for its biosimilars and that the FDA would then choose which preferred suffix met its guidelines. Sounds like a good policy, right? Companies get to suggest their favorite “baby” names and the FDA picks one it likes. Well, the FDA withdrew that plan on June 20, 2016.

However the suffixes for biosimilars have been chosen since June 2016, it was clear that the FDA only applied this requirement for suffixes (which makes sense for biosimilars, so that consumers can tell them apart and doctors can report adverse events) to biosimilars. For example, Sandoz’s Zarxio’s nonproprietary name is “filgrastim-sndz”. Totally logical so far.

On November 16, 2017, the FDA approved Genetech’s hemophilia A biologic Hemlibra (good news for patients!) and assigned it a random suffix of “kxwh” (emicizumab-kxwh).    In the absence of published public comments (which would be published in the Federal Register) and/or the announcement of a policy decision, one has to assume that assigning these suffixes to all new biologics will be the law of the land.

We know the time an effort industry sponsors put into branding their biologics and we imagine that random characters appended to the end of such a carefully-considered name is not the most welcome of surprises. The FDA typically provides sponsors with substantial notice prior to making substantive policy changes (it is a government agency after all!); however, this sort of abrupt implementation of policy may be our new normal.