Getting a clinical trial drug into an investigator site in China is a complex business. There used to be a perception that it could take a couple of years to get approval to run a trial, but timelines have reduced dramatically. China is working towards a 90-day process, and typically it takes between three and six months. For a biologic drug the process can take up to two years. It is within the interests of a sponsor to run its clinical trial in many countries across the world, taking in a wide demographic of patients with different ethnicities, ages, locations and genders in order to gain sufficient data. In order for the drug to eventually be marketed there it is imperative for a clinical trial to take place in China. There is a huge market in China, with approximately 19% of the world’s population and a projected expenditure on pharmaceuticals in 2018 of $170 billion, so local trials within the country are vital to any global organisation. Either setting up an office or finding a local company to act as the representative within China is crucial. Many aspects of the approval process and ongoing operations are best done by a company in China with local regulatory and cultural knowledge. China benefits from a centralised healthcare system, and with such a huge population and regional centres of excellence there is a large patient pool accessible very quickly for many diseases. Recruitment can normally be swiftly completed.
Once the authorities in China have agreed that the trial may go ahead, and the ethics committee has given its approval, sites and investigators need to be chosen and all the documents for the study set up. In common with all countries within a trial, clinical record forms are created, country and protocol specific labels designed, product packs manufactured, people trained up and an Interactive Response Technology (IRT) system put in place. Agreements need to be made with depot facilities, brokers etc. There are audits, quality and technical agreements and contracts and suchlike to put in place and many of these tasks may be best served by outsourcing to a contract research organisation.
Much of the time a packing company will prepare the clinical trial packs for either the entire study, or for individual countries. These may include a comparator drug. In many cases this has to be sourced within China, and is dependant on the requirements of the local regulatory body. Most studies nowadays are “active comparator” studies as it is considered unethical to give a placebo drug rather than an alternative treatment. Individual tablets need to look identical to the test drug, together with the blister packs and external packaging. Without the personal reference number and access to the database back at the CRO or parent company it is impossible for the patient or the physician to tell which the actual drug is and which the comparator is.
Probably the most important single document for importation is the Import Permit issued by one of the provincial and municipal drug authorities, for example the Beijing Food & Drug Administration (BDFA). Many documents are required for this and the local World Courier office can assist with the application. Once application has been made through one of the FDAs then all arrangements should be made to import though that authority rather than another port. This simplifies the clearance process.
Together with the permit the following documents must be presented for clearance to take place: Customs Invoice, copy of the airline paperwork (the Master Air Way Bill), Packing List, Certificate of Analysis, and Clinical Trial Approval which comes from the consignee together with a copy of their business license, and First Leg Document showing the batch / lot number as indicated on the invoice. There are many requirements for the customs invoice including the shipper and consignee's name, address, what the contents are, shipment commodity description, country of origin, expiry date, batch number, manufacturer company name and shipper company name. Every single one of these must match the same details on the inner packaging label on the packages. Any discrepancies lead to delays at customs and China Inspection & Quarantine.
Next requirement is a packing list and this is another place where attention to detail is imperative. The packing list has specific information needed including the number of pieces, net weight and gross weight. The boxes or thermal container system (TCS) has to be selected in advance for the contents. It is really important that this is not changed as customs expect these exact details and if anything changes then the import permit is invalidated, leading to significant delays.
It is strongly recommended that all the paperwork is sent over to the clearing point office at the relevant port of entry so that it can all be checked together with the importer of record (IOR) and customs before the application is made for the permit. Once everyone agrees that the paperwork is all in place and the import permit has been issued then the okay to send goes back to the origination.
An airline booking is strongly recommended for all pharmaceutical shipments. This ensures sufficient space in the cargo deck of the flight and storage in the airline temperature controlled area during customs and regulatory clearance.
In Beijing, as an example, it takes up to two days to clear customs, which can be extended if the shipment is selected for inspection. During this time arrangements are made for storage with the airline in a refrigerator, freezer or controlled ambient area whilst everything is processed. TCS are generally prequalified for 96-120 hours nowadays which should be an adequate time for the transport and clearance under normal circumstances but it is still recommended for all shipments to China to use Phase Change Material (PCM) to maintain temperature which can be re-charged without danger to the shipment in the appropriate area of the warehouse at the airport.
Generally a refrigerated/temperature-controlled truck is used to transfer shipments to a depot. The World Courier depot is located in Beijing which makes interactions with the BFDA much simpler. Temperature monitors inside the boxes can be downloaded immediately to ensure no temperature excursions have taken place. If there is a deviation then boxes can be placed into quarantine. Every minute outside specification requires investigation before the Qualified Person back at the manufacturer can confirm release status.
Every part of a shipment is counted off the list inside the handling area; pack numbers checked and re-checked, this is required for many regulations including GDP, the Drug Quality and Safety Act and the Falsified Medicines Directive to be sure of the pedigree of every item at every step of the way.
Meanwhile batch testing is done to establish the stability of product under extreme conditions. Boxes of drug sit in special chambers at frozen, refrigerated and controlled room temperature levels and extreme temperatures of up to 60°C, with differing levels of humidity and light to find out what will happen when patients take their supplies home and don’t necessarily follow any of the instructions about storage. During the lifetime of the study it is quite likely that the analysis of the stability data will show that the shelf life is longer than initially assigned. Fortunately something can be done about this and for shipments stored at the depot then specially trained operatives are permitted to get supplies out and apply new expiry date labels to every pack. Two people work together to ensure that everything is done correctly and a complete log is made of the entire process.
Over at the investigator’s site once a suitable patient attends and is enrolled in the trial, the site nurse or investigator can use the IRT system to check the central database and assign a pack under the randomisation criteria. The system generates a packing list, and for drug stored at a depot the drug is accessioned and then dispatched in a TCS to the investigator site for administration.
China requires extra attention to detail to ensure that everything is in place for seamless shipping, clearance and storage, necessary for successful supply to investigators and ultimately patients.