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To accelerate the improvement of China's drug technology guiding principle system, industry stakeholders should take the initiative to exert their strength

 Last Update: 2023-01-06
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In recent years, the Center for Drug Evaluation (CDE) of the State Medical Products Administration has been accelerating the formulation and issuance of drug technical guidelines, which not only provides strong technical support for scientific and fair decision-making, but also lays a foundation
for standardizing and guiding new drug research and development procedures and promoting the establishment of an innovation ecosystem 。 However, under the condition of limited resources, how drug regulatory agencies can effectively adapt to and meet the needs of the rapid development of the pharmaceutical industry, while taking into account the individualization of emerging technologies or cutting-edge technology research and development, and reasonably advance the layout, it is worth actively exploring by all parties in the industry, giving play to subjective initiative, and providing more basic support for regulatory agencies in the early stage of research and development, so as to accelerate the improvement of China's drug technology guiding principle system
.

I.
The concept and current status of the technical guidelines for medicines

Concept and current status of pharmaceutical technical guidelines

Technical guidelines for drugs refer to various technical specifications, guiding principles, technical guidelines and requirements related to drugs, which have guiding significance
for the development, production, operation and use of drugs.
Although the relevant documents are not administratively mandatory, they can still play an important role
in the process of drug development and registration.

Technical guidelines for pharmaceuticals

In its early days, the FDA issued a class of official, nonbinding documents called "guidelines" and later "guidance
.
" In 2011, FDA issued guidance for the establishment and requirements of the guidelines for the development of quality management strategies (Good Guidance Practices Policy (GGP), which clarifies how to develop and use guidelines and publishes reports to improve efficiency and transparency in the establishment of guidelines
.

In 2003, China's CDE organized and formulated the internal working procedures of the "Drafting and Revision of Technical Guidelines for Drug Research", and started the drafting of
technical guidelines for drugs.
The drug regulatory reform was initiated in 2015 and the ICH was joined in 2017, so that China's drug registration technical requirements are continuously harmonized with international rules
.

China's drug technical guidelines have grown explosively in the past three years
.
During the 13th Five-Year Plan period, CDE1 issued a total of 141 technical guidelines for drugs, and in 2021 alone, CDE issued 87 technical guidelines, and plans to add 480 new guidelines during the 14th Five-Year Plan period
.
As of 2022, according to the professional classification of ICH guidelines, China's common guiding principles system covers quality, effectiveness, multidisciplinarity, safety and other aspects, which is basically consistent with the EU, but there is a big gap
with the US FDA in terms of quality-related technical guidelines.
In terms of technical guidelines for personal medicines, compared with China and the European Union, the United States is far ahead
.

Table 1: FDA, EMA, NMPA common technical guidelines professional classification and quantity

Table 2: FDA, EMA, NMPA commonality and number of individual drug technical guidelines

Data source: Review and prospect of the construction of China's drug technology guiding principle system

(Chinese Journal of Pharmacovigilance, 2022, 19 (10): 1045-1049
.
)

Second, the value of guiding principles in drug innovation and research and development

The value of guiding principles in pharmaceutical innovation and development

1.
The guiding principles can focus on common problems, standardize and scientifically guide enterprise R&D and production

The formulation of guiding principles is not only a pre-task for regulators, but also an effective effort
to implement a large number of basic and common work on paper, reduce understanding bias, and reduce the difficulty and demand of later communication meetings.
For example, in 2021, CDE received 4,450 applications for communication and exchange meetings, a year-on-year increase of 37.
81%; 425 communication meetings were held throughout the year, a year-on-year increase of 58.
58%, of which 70.
35% were held at the key stage of drug research and development
.
In the face of the rapid increase in workload, CDE has held several meetings to discuss how to improve the quality of communication, and the establishment and promotion of guiding principles is an effective solution
.
The ideal scientific management system for review should be composed
of normative guidance in the early stage, communication and exchange in the middle stage, and final review decision-making.

The formulation and publication of CDE technical guidelines for drugs is of positive significance
to all parties involved in drug development.
For regulatory agencies, the guidelines can regulate the technical review criteria for drugs; For drug registration applicants, it is an effective support
to ensure the quality of research and development.
In addition, the guiding principles are also an important means to guide drug R&D and registration applications, and are the common basis
for communication between regulators and sponsors.
The "Guidelines for Clinical R&D of Clinical Value-oriented Antitumor Drugs" issued by CDE in 2021 clarifies in the background of the document that "new drug R&D should provide patients with better treatment options as the highest goal", guiding R&D to return to clinical value, avoiding waste of resources, enabling industry stakeholders to reconsider product project standards, and effectively promoting the healthy and sustainable development
of anti-tumor drug R&D activities in China.

2.
Take the lead in issuing guiding principles, which can influence the formulation of relevant international rules

In international exchanges, how to enhance the international influence and discourse power of Chinese drug regulators has attracted more and more attention
from the industry.
The formulation, publication, interpretation and training of guiding principles is a continuous and continuous work, and the more involved in the relevant work at an early stage, the more you can understand the overall background and considerations of the development of the document, and the more you can grasp the relevant management concepts and ideas
.

After China's accession to ICH, it has fully introduced the globally accepted technical requirements for drug R&D and registration, which has promoted the construction
of the domestic drug technology guiding principle system.
While drawing on international experience to formulate guiding principles, it is also our goal
to provide Chinese wisdom through exchanges and practices with other regulators and industry members.
For the field where there are no perfect management documents in the world, if the relevant guidelines can be issued in China and updated in time, it often means that the world's leading practical experience can be obtained in this field, and after this advantage is transformed into international standards, it has very positive significance
for all parties in China's industry 。 Taking the lead in issuing guidelines and proposing project proposals to ICH will help regulators form an industry reputation and promote the translation of China's drug registration technical requirements into international rules in the future; For drug registration applicants, using internationally accepted standards to carry out R&D can reduce the technical barriers and R&D costs of international R&D registration, and help them quickly enter the international market; For patients, it will help new drugs at home and abroad to be launched as soon as possible, so that patients can get the opportunity
to use the world's leading drugs as soon as possible.

3.
Improving the efficiency of guiding principle issuance is a continuous demand of industry stakeholders

Improving the efficiency of guiding principle issuance is a continuous demand from industry stakeholders

1.
In terms of release timeliness, the speed of CDE guidelines still cannot meet all needs

In recent years, under the guidance of the national innovation-driven strategy, the process of independent drug innovation in China has accelerated significantly, the R&D capacity of pharmaceutical innovation has been rapidly improved, and the number of innovative drugs on the market and the number of clinical trials of new innovative drugs have increased significantly (Figure 1).

Rapidly growing R&D needs are increasingly at odds
with the limited guiding principles development plans of the review body.

On the whole, on the one hand, with limited human resources, CDE has limited room to continue to accelerate the development of guiding principles, and at the same time, it needs to be formulated
according to the work plan in order.
On the other hand, guided by the goal of market gaps and cutting-edge technologies, industry stakeholders have a high degree of sensitivity to market demand, but regulators cannot directly obtain front-line information and are difficult to identify its importance in the early stage of innovative product development, and then cannot include it in the work plan in a forward-looking manner to organize relevant experts to form a first draft
of the document.
How to provide regulatory review institutions with more "industry-university-research" information with an international perspective in addition to the information of past review experience and accelerate the establishment of relevant specifications is also a problem
that industry stakeholders need to think about in depth.

Figure 1: IND and NDA approvals of innovative drugs in China from 2017 to 2021

Source: 2021 Drug Evaluation Report (NMPA)

2.
In terms of coverage, the demand for guiding principles by industry stakeholders is decentralized and advanced

With the continuous deepening of the reform of the review and approval system, local pharmaceutical innovative enterprises have taken the first step
from rapid follow-up to original innovation.
It cannot be ignored that in the actual clinical research and development process, there are still many problems such as the lack of close integration of research direction and clinical needs, and omissions in research design, and there are still many areas that need targeted guidance
.

Taking diabetes and metabolic diseases as an example, China's relevant technical guidelines have made significant progress compared with the United States and Europe in terms of richness and update time (see Table 3).

However, with the rapid development of China's innovative drug research and development industry, there are still many unmet needs
.

Table 3: Guidelines for diabetes and metabolic diseases

Source: Compiled by the Clinical Research Committee of Diabetes and Metabolic Diseases of the Chinese Association for the Promotion of Medicine

Some of the guiding principles are internationally documented, but have not yet been included in the development plan in China

The US FDA has issued several guidelines on the evaluation of bioequivalence of biologics since 2001, and the European Medicines Agency issued guidelines on the evaluation of the bioequivalence of human insulin and its analogues in 2015, both of which clearly state that the positive glucose clamp test
is required to evaluate the bioequivalence of insulin preparations 。 The domestic NMPA Drug Review Center published an article in 2012 to discuss the key points that should be paid attention to in the study of PK/PD of insulin preparations, but the high insulin normal glycemic glucose clamping technology recommended in the article is rarely used internationally, and there is still a lack of overall guidelines
for evaluating the pharmacokinetics, pharmacodynamics and safety of insulin biosimilars in clinical trials.

There are also some guiding principles that are not mature internationally

Type 1 diabetes (type 1 Diabetes, T1D), although less common than type 2 diabetes, mainly affects adolescents and young adults
.
Insulin or insulin analogues are the mainstay of treatment for T1D
.
However, this class of drugs is injected subcutaneously, the treatment is cumbersome, and the factors affecting dose adjustment are many and extremely individualized
.
In addition, treatment with insulin or insulin analogues does not alter the progression
of T1D.
At present, the FDA has approved pramlintide as an adjuvant therapy for type 1 diabetes, and the CD3 antibody Teplizumab will also be approved in the near future to delay the onset of type 1 diabetes (T1D)
in high-risk individuals.
The EMA approved dapagliflozin and sopagliflozin for T1D
with a BMI of ≥27 kg/m2 and poor glycemic control after insulin therapy.
China has not approved any non-insulin or insulin analogue drugs for the treatment
of T1D.
China urgently needs a technical guideline for the research and development of non-insulin drugs for type 1 diabetes to encourage pharmaceutical companies to develop relevant drugs
in this field.

The field of cutting-edge technology is constantly evolving and iterating

In some cutting-edge technology fields, China's regulatory policies have been in line with developed countries, but based on the rapid development of policy formulation, it is still necessary to continuously improve management points according to R&D progress and application, and coordinate relevant regulatory standards
internationally 。 For example, in the field of cell and gene therapy (CGT), China has successively issued three guiding principles this year: "Technical Guidelines for Pharmaceutical Research and Evaluation of In Vitro Gene Modification Systems (Trial)", "Technical Guidelines for Pharmaceutical Research and Evaluation of In Vivo Gene Therapy Products (Trial)" and "Technical Guidelines for Pharmaceutical Research and Evaluation of Immune Cell Therapy Products (Trial)", but the rapid progress of technology will not only bring rapid breakthroughs in product research and development, but also make supervision face more problems
.

4.
Industry parties may participate in the establishment and revision of the guiding principles

Industry stakeholders can participate in the establishment and revision of the guiding principles

1.
Industry stakeholders have been involved many times in the process of developing the guiding principles

From early project establishment to formal release, throughout the process of establishing the guiding principles, most of the relevant parties in the industry at this stage will only participate in the solicitation of
opinions in the later stage of the formulation of the guiding principles.

Taking the drafting process of ICH guidelines as an example (Table 4), industry stakeholders generally participate in the formulation of guidelines at the Step3 stage as the proposers for comments, but in essence, at the initial stage of project establishment, the ICH Secretariat has begun to receive new work project proposals from ICH members and observers (national drug regulatory agencies), and submit them to the ICH Management Committee for approval after review and revision, and finally drafted by an informal expert group to form a concept paper
。 Overall, the proposal of new projects, the development of concept documents, and the integration of opinions into final documents are very important links in the ICH guiding principle development process, which require the participation of industry stakeholders at different levels
.

Table 4: ICH Guiding Principles Drafting Process

Source: ICH official website information

2.
Industry stakeholders can provide valuable advice in key aspects of the development of guiding principles

For the establishment of the ICH guiding principles, the concept paper (concept paper) is often considered to be an important stage between ideas and guidelines, and it is also a bellwether
for the trend of international drug regulation.
The content of the concept paper document generally includes: the method of writing (updating or rewriting in the existing guidance), the existing situation, the problems to be solved, the development of relevant international policies, the resources and types of expert groups, the time of writing
, etc.

In the CDE guideline project establishment stage, there is also a link of drafting according to the plan after the project is established, and the drafting group will be established and a draft
document will be formed in the process of drafting the guiding principles.
In the drafting notes of the Guidelines for Quantitative Methodology for Extrapolating Adult Drug Data to Pediatric Population (Draft for Comments), it was introduced that its drafting group was established based on the strategic cooperation between the Center for Drug Review and Southern Medical University, and the members were composed of representatives from academia, pharmaceutical industry and evaluation institutions, and that this ensured the efficient and high-quality completion
of the guiding principles.

FDA, which has different processes in different centers, mentioned in its 2011 Good Guidance Practice Report – Improving Efficiency and Transparency that FDA's GGP regulations clearly provide that stakeholders can submit recommended guiding principles topics and/or draft recommended guiding principles
.
Stakeholders may also submit a citizen petition to identify policy issues
that the administration may decide to address by issuing guidelines.
While FDA also cannot guarantee timely guidance, the channels and processes are clearly defined
.
The report mentions that the center already receives draft
guidance submitted by stakeholders to regulators through industry events, associations, and the FDA's website.
Submitting drafts rather than just suggesting guidance topics can give regulators a better understanding of the situation and expedite the development of guidelines, especially when
new scientific issues are involved.

5.
Industry stakeholders should initiate / participate in the establishment of guiding principles at an early stage

Industry stakeholders should initiate / participate in the establishment of guiding principles at an early stage

1.
Industry organizations and the pharmaceutical industry should take the initiative to provide more basic information for regulatory decisions

In the existing project establishment process, the regulatory authority proposes a guiding principle project plan
on an annual basis based on the review experience and the application of international guiding principles.
In addition, with reference to the procedures of the ICH Secretariat for receiving new work items proposed by national drug regulatory agencies, China's regulatory authorities can also consider receiving relevant suggestions
from qualified domestic industry organizations.
Industry associations, doctors and patient organizations can use the power of the platform to discuss with the pharmaceutical industry and provide the required research information and suggestions
according to the actual situation and resources more comprehensively and objectively.

In the promotion of international regulatory policies, the China Association for the Promotion of Pharmaceutical Innovation actively participates in the recommendation and coordination of ICH experts
.
As of October 2022, as a member of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), the China Association for the Promotion of Pharmaceuticals has jointly submitted to IFPMA The 23 ICH expert working groups recommended 45 experts (including 14 team leaders and 9 alternate team leaders), representing 53%
of the total number of IFPMA global experts.
(See link "The 11th Asian Regulatory Conference: The Role of the China Pharmaceutical Promotion Association in ICH Work")

In the promotion of domestic regulatory policies, based on the understanding of patient needs and industrial pain points, and the continuous implementation of the work concept of "industry-university-research and use of funds" closely integrated by the CPPC, the Clinical Research Professional Committee of Diabetes and Metabolic Diseases of the China Association for the Promotion of Pharmaceutical Innovation has formally submitted an application to CDE to assist in the formulation of two guiding principles: "Technical Guidelines for the Development of Non-insulin Drugs for Type 1 Diabetes" and "Guidelines for the Evaluation of Insulin Pharmacokinetics and Pharmacodynamics by Clamp Test", and has been supported.
Draft guiding principles are under discussion
.

2.
Industry stakeholders should establish cooperative contacts with regulators in the early stage of R&D

The drafting of guiding principles is often the most difficult and time-consuming part of the entire guiding principles development process, and all parties in the industry can give full play to their advantages to participate in the early stage of the formulation of guiding principles, accelerate the formulation and release of regulatory authorities by providing draft documents, and jointly improve and promote the established standards
in international exchanges.
Uniting industrial forces to formulate R&D guidelines in the form of social co-governance will not only be an effective solution to increase the applicability of guidelines and improve work efficiency, but also an important means
to break through the limited review resources of regulatory agencies and compete with international leading institutions.

Independent innovation often cannot be achieved through "waiting for what is needed", and it is the common responsibility
of every stakeholder in the pharmaceutical research and development process to concentrate all parties in the industry to break through the R&D barrier.

Policy Research Center, China Association for the Promotion of Pharmaceutical Innovation

Author: Lianghui Tong, Assistant Researcher tonglh@phirda.
com

Review proofreader: Zhang Zhijuan, Liu Fapeng

Resources:

1.
Review and prospect of the construction of China's drug technology guiding principle system (China Pharmacovigilance, 2022, 19 (10): 1045-1049
.

2.
Fact Sheet: FDA Good Guidance Practices

3.
The drug review center held a symposium to improve the communication and exchange mechanism and service enterprises

3.
The drug review center held a symposium to improve the communication and exchange mechanism and service enterprises 4.
The 2021 drug evaluation report

4.
The 2021 drug evaluation report 5.
Formal ICH Procedure

5.
Formal ICH Procedure

6.
Background: Report on Good Guidance Practices

7.
Guiding principles column

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