hrough compassionate use programs (otherwise known as named patient programs or special access schemes), patients suffering from critical, life-threatening conditions can access potential life-saving therapeutic options which have not been formally approved by the responsible health authority in an ethical and regulated way. Many health authorities in Asia Pacific (AP) have defined the compassionate use of unapproved therapeutic products in their pharmaceutical acts or regulations so that medical practitioners can request, on behalf of their patients, the import of unapproved medicines for treatment.

Background

Regulations and laws govern use of unapproved investigational products under specific circumstances. These include life-threatening conditions for which there are no alternative effective or available treatment options; in some instances, only therapeutics involved in the final stages of the clinical trials, which have demonstrated sufficient evidence of efficacy, safety and quality, are utilized.

Compassionate Use Programs (CUPs) provide an ethical and valuable pathway for patients with life-threatening conditions to gain access to investigational drugs, biologics, and medical devices not yet approved in their market. These programs are generally intended for patients who are not eligible for clinical trials or have no therapeutic product commercially available in their market. Compassionate use is a term adopted by the European Medicines Agency and is synonymous to the US FDA’s Expanded Access.

The basis of these programs is similar but different markets use different terminologies, such as Compassionate Use Program (CUP), Named Patient Program (NPP), or Special Access Scheme (SAS). CUPs around the globe differ between each local market but generally require various prerequisites to be met.

National CUP, NPP, or SAS Regulation in Asia Pacific

• Category A is a notification pathway which does not require TGA’s approval and is intended for seriously ill patients whose death is reasonably likely to occur within a matter of months or occurrence of premature death is likely in the absence of early intervention.
• Category B is an application pathway that requires TGA’s approval; it is dedicated to patients who do not fit into Category A and cannot access the unapproved good through Category C because the product does not have an established history of use.
• Category C is a notification pathway that does not require TGA and allows the supply of goods to the patient if that product has a well-established history of use.
• Notification pathways require a copy of the respective category forms to be sent to TGA within 28 days of the therapeutic goods being supplied to the patient.

In China, compassionate use is generally defined in the Drug Administration Law effective in 2019: “For drugs under clinical trial which are used for the treatment of serious life-threatening diseases for which there are no effective treatment and medical observations concluded that such drugs are beneficial and comply with ethical principles, such drugs may be used within the clinical trial institution on other patients with the same condition upon review by ethics committee and obtained patient informed consent.” The National Medical Products Administration (NMPA) has recently revised Regulations for the Implementation of the Drug Administration Law to supplement the conditions described in the Drug Administration Law: (1) physicians can offer the suggestion of compassionate use, provided that medical analysis has been made on the patient’s conditions, proving that the benefits may outweigh the risks, and the patient cannot participate in the clinical trials of drugs; and (2) the investigational drugs for compassionate use shall follow the patient’s voluntary request and conform to the principles of medical ethics and informed consent. After ethics committee review and approval, physicians with experience in using the investigational drugs or relevant training can administer the drugs in patients with similar conditions in the institution implementing the clinical trials.

These articles may be updated in the final regulation. However, guidelines for detailed procedures and requirements have not yet been issued. Although the former CFDA (currently known as NMPA) issued a draft version of Provisions on Management of Investigational Drugs for Expanded Compassionate Use for public comments in 2017, the content may be updated in the future.

Regarding compassionate use of drugs which have been approved in certain markets but not by the NMPA, the following policies have been effective:

(1) Since 2018, a pilot program has empowered the Hainan provincial government to approve the import of a small number of drugs (excluding vaccines), which have been approved overseas or approved by key ICH Member Agencies, to be used in designated medical institutions in Hainan Boao Lecheng International Medical Tourism Pilot Zone for urgent clinical needs.

(2) Since 2020, a pilot program has empowered the Guangdong provincial government to approve drugs that meet urgent medical needs and are already marketed in Hong Kong and Macau for use in designated hospitals in nine cities in the Greater Bay Area of Guangdong Province.

(3) Since June 2022, the Work Plan for Temporary Import of Drugs Urgently Needed in Clinical Practice issued by the National Health Commission allows medical institutions to apply for temporary import of a small number of drugs that have been approved overseas but not approved or manufactured in China for urgent clinical needs.

In Hong Kong, NPP is regulated by the Pharmacy and Poisons Regulation Cap 138, 36(1A) where exemption of registration is applicable if a pharmaceutical product is intended for the sole purpose of treating a particular patient by a registered medical practitioner. Such drugs which are not registered in Hong Kong can be used on certain named patients where the medical practitioner must obtain prior endorsement and inform the patients on use of the unregistered pharmaceutical product and any accompanying adverse effects they might observe.

In India, GSR354E, 5 June 2020 (draft), underpins importation of unapproved new drugs for compassionate use by hospitals or medical institutions in the treatment of patients. India’s regulatory framework for compassionate use allows any medical practitioner or government medical organization to import a new unapproved drug for compassionate use by applying to the Central Drugs Standard Control Organization (CDSCO). For patients suffering from diseases which are life-threatening or may cause serious permanent disability, or patients requiring treatment for an unmet medical need, new drugs which have not been permitted within India but are undergoing a phase 3 clinical trial in any market can be imported exclusively for compassionate use once certified by CDSCO. CDSCO will review and process these applications within 30 days.

In Indonesia, the National Agency of Drug and Food Control (NADFC, also known as BPOM) promulgated guidance No. HK.00.05.3.00914 to depict Indonesia’s SAS. Although not explicitly stated, the scope of this SAS is mainly intended for biological products. Unapproved biological products can be used and imported to Indonesia on a case-by-case basis if it is intended for special therapeutic purposes and authorized by NADFC. Physicians can apply to NADFC for SAS by providing suitable scientific justification such as treatment of life-threatening diseases, available drugs in Indonesia are inadequate to treat the patients, or drugs are unavailable due to supply issues or rescinded distribution licenses. Drugs imported via these SAS must demonstrate evidence of their effectiveness, safety, and quality, and the quantity of the imported drug should not exceed 12 months’ worth of doses. NADFC will issue the import license for the unapproved drug within 10 working days from receipt of the application documents.

Separately, the Ministry of Health (MoH) of the Republic of Indonesia established guidance No. 1379A/MENKES/SK/XI/2002, which depicts SAS for drugs and medical devices that have not been approved but are needed to support community health services. The basis for the need for such drugs and medical devices should be presented by a qualified physician based on scientific justification and in coordination with a teaching hospital. Two classifications of drugs qualify for SAS: Orphan Drugs (a drug needed to treat a rare disease, defined as an incidence rate of less than 200,000 patients in Indonesia) and drugs with low commercial value (regardless of indication). The presenting physician should also categorize patients based on clinical condition: Category A for patients suffering from terminal or severe and life-threatening condition, or Category B for all patients not included in Category A. The MoH will process each request based on these classifications.

In Japan, the equivalent of compassionate use was established in January 2016, designated as expanded access clinical trials which are those conducted on an ethical basis. Expanded access trials leverage the standard clinical trial framework and adhere to similar laws and regulations. This process focuses on investigational products in the final stages of clinical trials before marketing authorization. Any undesirable effect observed in the expanded access trials will not impede or delay the main clinical trial. Moreover, it provides strong recommendations for expanded access clinical trials for drugs that are expected to be in high patient and societal demand. The Pharmaceuticals and Medical Devices Agency (PMDA) cites four scenarios for high patient and societal demand: drugs already in the US expanded access program, Sakigake-designated drugs, orphan drugs, and drugs requested by the Expert Committee for Unapproved Drugs. (Sakigake is approximately analogous to FDA’s Breakthrough Therapy designation and to EMA’s PRIME designation, with some important differences.) Sponsors will decide if they wish to conduct expanded access trials based on requests from medical institutions and patients.

A physician can also administer single-patient use of an unapproved drug. These physicians must submit documents through their regional office of the Ministry of Health, Labour and Welfare (MHLW), consult with a review board, and submit a study plan to relevant databases such as the Japan Registry for Clinical Trials (jRCT). This framework and process, even for the use of an unapproved drug for treatment of a single patient, is equivalent to that of a clinical trial. Japan also offers a “Patient requested system for unapproved drug” as authorized clinical research, led by medical institutions based on a protocol for off-label use of approved drugs.

In Malaysia, according to the provisions of regulation 15(6) under Control of Drugs and Cosmetics Regulations 1984 under the Sale of Drugs Act 1952, hospitals or physicians who wish to import or manufacture any product for the sole purpose of treating a patient suffering from a life-threatening illness may apply for exemption of license registration with the Director of Pharmaceutical Services, Ministry of Health. When an unregistered product is used or a registered product is used off-label, the physician is fully responsible for its use and must provide sufficient explanation to the patient. Patient consent is needed prior to initiation of treatment. Compassionate use, also referred to as named patient program, is also available as an extension to an approved clinical trial protocol. However, this program only allows patients already enrolled in the approved clinical trial to qualify for use of the unregistered medicinal product. The criteria for application under compassionate use program includes treatment meant for patients with serious or immediate life-threatening condition, no comparable alternative therapy, epidemic cases, orphan disease, and potential benefit justifies the potential risk of the treatment (treatment would not expose patient to unreasonable significant risk). Available clinical evidence of safety and efficacy must also be shown. Exemption applications are reviewed at the discretion of the Pharmaceutical Services Programme.

In New Zealand, the Medicines Act 1981 Section 25 and 29 governs the supply and procurement of unapproved medicines. The exemption provisions in Section 25 allow all authorized prescribers (nurses, optometrists, dentists, registered midwives, and designated prescribers) to obtain an unapproved medicine for a known patient under their care via direct importation, or by asking a pharmacy to compound a medicine, but are not allowed to prescribe unapproved medicines to patients. On the other hand, provisions in Section 29 permit the sale or supply of unapproved medicines to a registered medical practitioner for the treatment of a patient under that medical practitioner’s care, and medical practitioners can prescribe unapproved medicines that have been manufactured in or imported into New Zealand. Section 29 requires these practitioners to send relevant patient and medicinal information back to the importer or manufacturer of the unapproved medicine, who are then required to send information to Medsafe the month after supplying this medicine.

In the Philippines, compassionate drug use is legal and tightly regulated. It is intended for people who meet certain specific criteria of critically ill patients. Compassionate Special Permit (CSP) is granted by the Philippine FDA to allow unapproved investigational drugs to be used for critically ill patients. The Philippine FDA approved the process in 1992 and provides special access to these products if it is morally and ethically justified and there is no existing alternative therapy to treat or adequately control their conditions. The CSP can be requested for an individual patient or for institutional use.

In Singapore, import and supply of unapproved therapeutic products for patient use can be approved through the Special Access Route (SAR). The Singapore Health Sciences Authority (HSA) will consider approving life-saving therapies for an unmet medical need (for example, if a registered treatment option is absent) if the patient’s health will be clinically compromised without using the unregistered therapeutic product. Requesting physicians are fully responsible for this use. HSA targets 14 working days, excluding stop-clock time if additional information or clarification is needed, to approve these applications.

In South Korea, compassionate use is defined in articles 28 and 29 of the Regulation on Safety of Pharmaceutical Drugs and in paragraph 4 of Article 34 of the Pharmaceuticals Affairs Act. These articles define the “Permission for Use of Investigational Products for Treatment Purposes” intended for emergency patients. Under the Pharmaceuticals Affairs Act, unapproved pharmaceuticals planned for compassionate use outside of clinical trials can be leveraged for treatment purposes if patients are suffering from a life-threatening disease (e.g., terminal cancer, acquired immunodeficiency syndrome) or equally serious or urgent life-threatening condition, or no alternative therapy is available during this critical therapeutic window that warrants the need for immediate treatment. The Ministry of Food and Drug Safety (MFDS) reviews and grants permission for compassionate use for an individual patient and/or groups of patients. Approval time varies by application type: seven days for an individual, 30 days for more than two patients.

In Taiwan, compassionate use is defined in Article 48-2 of the Pharmaceutical Affairs Act and the Ministry of Health and Welfare announcement of Regulations for Approval of Specific Medicinal Products’ Manufacturing or Importing as a special case in 2016. To prevent or treat life-threatening diseases or if there is no treatment available domestically, teaching hospitals above the regional level and psychiatric teaching hospitals can apply to Taiwan FDA for approval to import an unregistered drug into Taiwan.

In Thailand, the patient use program is defined in Section 13(5) of the Drug Act B.E. 2510 (1967), which allows public hospitals, the Thai Red Cross, government pharmaceutical organizations, or governmental bodies responsible for disease treatment to import drugs that are not registered in Thailand. Through this pathway, physicians can request the importation of unapproved and unlicensed drugs for specific patients, subject to Thai FDA approval.

In Vietnam, there is currently no regulated program for compassionate use. However, under Decree 54/2017/ND-CP, Article 68, adopted by the National Assembly of Vietnam and in effect from July 1, 2017, drugs used for special treatment based on hospital demand can be imported without marketing authorization if they are granted import licenses. These import licenses are inclusive of unlicensed drugs for special hospital medical treatment needs. The import company will submit the dossier for the import of the unapproved drug on behalf of the hospital to the Drug Administration of Vietnam (DAV), and the hospital’s treatment committee will issue a letter to justify the demand and provide estimated patient numbers and proposed drug amounts. DAV will process the import license within 60 working days.

Summary of AP Landscape: Evolve and Change

Some markets within Asia Pacific have defined and stipulated the use of unapproved drugs for life-threatening conditions in their pharmaceutical acts or regulations, but others lack well-established guidelines promulgated for healthcare professionals or sponsors to reference. Criteria and prerequisites for compassionate use of unapproved drugs are for the most part similar among these different markets. For example, patients must meet specific criteria (e.g., suffering from a life-threatening condition, no alternative available therapy, unapproved drugs have demonstrated sufficient efficacy and safety, etc.) before they are eligible for these pathways. Review and approval timelines differ for each market, with the duration ranging from two to three working days to a few weeks, and some markets have no specified timeline. Most experts report the general review and approval timeline to be approximately two to four weeks. The regulatory landscape of compassionate use continues to evolve and change in Asia Pacific; for example, NMPA published a new draft guidance in 2022 which elaborates on compassionate use in China.

Generally, the required documents, prerequisites, and review processes are relatively straightforward and well-defined, and offer reasonable approval timelines that give patients in Asia Pacific one more chance to address their unmet medical needs.

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